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Benaroua C, Pucci F, Rooman M, Picod A, Favory R, Legrand M, Vincent JL, Creteur J, Taccone FS, Annoni F, Garcia B. Alterations in the renin-angiotensin system during septic shock. Ann Intensive Care 2025; 15:40. [PMID: 40126750 PMCID: PMC11933633 DOI: 10.1186/s13613-025-01463-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Accepted: 03/13/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Alterations in the classical Renin-Angiotensin Aldosterone System (RAAS) have been described during septic shock and are associated with patient outcomes. Since the alternative RAAS has also been reported to be altered in critically ill patients, and given that the RAAS can be modulated by specific therapeutics, such as angiotensin II, understanding its pathophysiology is of primary interest. OBJECTIVE To describe the alterations in the classical and alternative RAAS during septic shock in comparison with healthy controls. METHODS This prospective, monocentric, controlled study enrolled 20 patients fulfilling the septic shock diagnosis, as defined by the Sepsis-3 criteria, along with 30 controls. The main exclusion criteria were the use of any prior medication modifying the RAAS, prior liver failure (Child-Pugh score > 9), or chronic kidney disease (estimated glomerular filtration rate < 30 ml/min/1.73 m²). Equilibrium concentrations of RAAS peptides were analyzed using a liquid chromatography-mass spectrometry method from heparinized plasma. Circulating angiotensin-converting enzyme (cACE), cACE type 2 (cACE2) activities, and circulating dipeptidyl peptidase 3 (cDPP3) concentrations were assessed. Values were measured at diagnosis, 6 h after diagnosis and on days 1 and 3. The main timepoint of interest was 6 h after diagnosis. Values 6 h after diagnosis were compared to 30 controls. RESULTS In septic shock patients, increased concentrations of the main peptides of the classical and alternative RAAS were observed compared to controls, particularly angiotensin I (Ang I) and angiotensin-(1-7) (Ang-(1-7)). Additionally, there was a significant increase in the Ang I/Ang II ratio (1.16 [0.74-3.31] vs. 0.34 [0.25-0.43], p < 0.05) and the Ang-(1-7)/Ang II ratio (0.15 [0.08-1.30] vs. 0.03 [0.02-0.04], p < 0.05). We also observed a significant reduction in cACE activity (3.38 [2.29-6.8] vs. 7.89 [6.39-9.05] nmol Ang II/L/h), an increase in cACE2 activity (814 [669-1987] vs. 214 [132-293] pmol Ang-(1-7)/L/h), and increased cDPP3 concentrations (54.6 [35-142.2] ng/mL vs. 13.7 [11.9-15.4] ng/mL, all p < 0.05). CONCLUSIONS Septic shock was associated with increased Ang I/Ang II and Ang-(1-7)/Ang II ratios, along with reduced cACE activity, increased cACE2 activity, and elevated cDPP3 concentrations compared to healthy controls.
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Affiliation(s)
- Camille Benaroua
- Department of Intensive Care, Erasme Hospital, Hôpital Universitaire de Bruxelles, Université libre de Bruxelles (ULB), Brussels, Belgium
- Department of Intensive Care, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Fabrizio Pucci
- BIO-Computational Biology and Bioinformatics, Université Libre de Bruxelles, Brussels, 1050, Belgium
| | - Marianne Rooman
- BIO-Computational Biology and Bioinformatics, Université Libre de Bruxelles, Brussels, 1050, Belgium
| | - Adrien Picod
- Université Paris Cité, UMR-S 942, INSERM, MASCOT, Paris, France
| | - Raphaël Favory
- Department of Intensive Care, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Matthieu Legrand
- Department of Anesthesia and Perioperative Care, Division of Critical Care Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Jean-Louis Vincent
- Department of Intensive Care, Erasme Hospital, Hôpital Universitaire de Bruxelles, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Jacques Creteur
- Department of Intensive Care, Erasme Hospital, Hôpital Universitaire de Bruxelles, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Fabio Silvio Taccone
- Department of Intensive Care, Erasme Hospital, Hôpital Universitaire de Bruxelles, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Filippo Annoni
- Department of Intensive Care, Erasme Hospital, Hôpital Universitaire de Bruxelles, Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Bruno Garcia
- Department of Intensive Care, Erasme Hospital, Hôpital Universitaire de Bruxelles, Université libre de Bruxelles (ULB), Brussels, Belgium.
- Department of Intensive Care, Centre Hospitalier Universitaire de Lille, Lille, France.
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Kotani Y, Lezzi M, Murru CP, Khanna AK, Zarbock A, Bellomo R, Landoni G. The Efficacy and Safety of Angiotensin II for Treatment of Vasoplegia in Critically Ill Patients: A Systematic Review. J Cardiothorac Vasc Anesth 2025; 39:653-665. [PMID: 39800604 DOI: 10.1053/j.jvca.2024.12.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 12/01/2024] [Accepted: 12/16/2024] [Indexed: 03/21/2025]
Abstract
OBJECTIVES To summarize evidence regarding intravenous angiotensin II administration in critical illness and provide an updated understanding of its effects on various organ dysfunction and renin-angiotensin system (RAS) biomarkers. DESIGN A systematic review. SETTING A search of PubMed, Embase, and the Cochrane Library from inception to May 3, 2024. Randomized controlled trials (RCTs), nonrandomized trials, quasi-randomized trials, observational studies, case reports, and case series were included. Comparative studies (RCTs and observational studies with comparator) were used for the main analysis. PARTICIPANTS Critically ill adults and children. INTERVENTIONS Intravenous angiotensin II administration. MEASUREMENTS AND MAIN RESULTS Fifty-nine studies with a total of 2,918 participants (5 RCTs, 15 observational studies, and 39 case reports or case series) were analyzed. Septic shock and cardiac surgery were the most common clinical conditions (14 studies for each). In 14 comparative studies (5 RCTs and 9 observational studies), mortality was not different from that in controls, except in 1 observational study. Several studies reported decreased renal replacement therapy use, improved oxygenation and blood pressure response, and decreased rate of myocardial injury with angiotensin II therapy. There was no increase in thrombotic events or adverse events. Angiotensin II therapy reduced renin and angiotensin I levels without affecting other RAS biomarkers. CONCLUSIONS Intravenous angiotensin II has been reported in almost 3000 critically ill patients with diverse types of shock. Despite unclear mortality impacts, angiotensin II seems to confer beneficial effects on several organ systems and RAS derangements, without increasing adverse events.
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Affiliation(s)
- Yuki Kotani
- Department of Intensive Care Medicine, Kameda Medical Center, Kamogawa, Japan
| | - Martina Lezzi
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Carlotta Pia Murru
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Ashish K Khanna
- Section on Critical Care Medicine, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC; Perioperative Outcomes and Informatics Collaborative, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC; Outcomes Research Consortium, Houston, TX
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, Muenster, Germany
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Hospital, Melbourne, Australia; Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia; Department of Critical Care, Melbourne Medical School, The University of Melbourne, Melbourne, Australia
| | - Giovanni Landoni
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.
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Chappell MC, Schaich CL, Busse LW, Clark Files D, Martin GS, Sevransky JE, Hinson JS, Rothman RE, Khanna AK. Higher circulating ACE2 and DPP3 but reduced ACE and angiotensinogen in hyperreninemic sepsis patients. Clin Sci (Lond) 2025; 139:43-53. [PMID: 39699964 DOI: 10.1042/cs20242168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/13/2024] [Accepted: 12/19/2024] [Indexed: 12/21/2024]
Abstract
Sepsis and septic shock are global healthcare problems associated with high mortality rates. Activation of the renin-angiotensin-aldosterone system (RAAS) is an early event in sepsis, and elevated renin may be predictive of worse outcomes. In a subset of sepsis patients enrolled in the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial, elevated levels of active renin (median value > 189 pg/mL or 5.1 pM) at baseline (day 0) were strongly associated with mortality; however, corresponding plasma levels of the vasopressor hormone Angiotensin II were not substantially increased nor was Angiotensin II associated with disease severity. The current study assessed RAAS components that may impact the Angiotensin II response in control subjects, normal renin sepsis (NRS, renin < 5.1 pM) and high renin sepsis (HRS, renin > 5.1 pM) patients. NRS and HRS subjects exhibited a similar reduction in ACE (40%), but increased levels of ACE2 and DPP3. The ACE to DPP3 ratio was higher in controls but this relationship was reversed in both NRS and HRS subjects. Intact angiotensinogen was 50% lower in the HRS than control or NRS subjects, whereas the intact angiotensinogen to renin ratio was <10% of control or NRS subjects. We conclude that altered expression of ACE, ACE2, DPP3 and angiotensinogen may attenuate the expected increase in Angiotensin II, particularly in sepsis subjects with high renin concentrations.
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Affiliation(s)
- Mark C Chappell
- Hypertension Center, Wake Forest University School of Medicine, Winston-Salem, NC
| | | | | | - D Clark Files
- Department of Internal Medicine, Section of Pulmonary, Critical Care, Allergy, and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, NC
| | - Greg S Martin
- Pulmonary and Critical Care, Emory University School of Medicine, Atlanta, GA
| | | | | | | | - Ashish K Khanna
- Hypertension Center, Wake Forest University School of Medicine, Winston-Salem, NC
- Department of Anesthesiology, Section on Critical Care Medicine, Wake Forest University School of Medicine, Winston-Salem, NC
- Outcomes Research Consortium, Cleveland, OH
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Legrand M, Khanna AK, Ostermann M, Kotani Y, Ferrer R, Girardis M, Leone M, DePascale G, Pickkers P, Tissieres P, Annoni F, Kotfis K, Landoni G, Zarbock A, Wieruszewski PM, De Backer D, Vincent JL, Bellomo R. The renin-angiotensin-aldosterone-system in sepsis and its clinical modulation with exogenous angiotensin II. Crit Care 2024; 28:389. [PMID: 39593182 PMCID: PMC11590289 DOI: 10.1186/s13054-024-05123-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/05/2024] [Indexed: 11/28/2024] Open
Abstract
Dysregulation of the renin-angiotensin-aldosterone-system (RAAS) in sepsis is a complex and early phenomenon with a likely significant contribution to organ failure and patient outcomes. A better understanding of the pathophysiology and intricacies of the RAAS in septic shock has led to the use of exogenous angiotensin II as a new therapeutic agent. In this review, we report a multinational and multi-disciplinary expert panel discussion on the role and implications of RAAS modulation in sepsis and the use of exogenous angiotensin II. The panel proposed guidance regarding patient selection and treatment options with exogenous angiotensin II which should trigger further research.
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Affiliation(s)
- Matthieu Legrand
- Department of Anesthesia and Perioperative Care, Division of Critical Care Medicine, University of California San Francisco, 521 Parnassus Avenue, San Francisco, CA, 94143, USA.
| | - Ashish K Khanna
- Department of Anesthesiology, Section on Critical Care Medicine, Wake Forest School of Medicine, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
| | - Marlies Ostermann
- Department of Critical Care, Guy's and St Thomas' Hospital, London, UK
| | - Yuki Kotani
- Department of Intensive Care Medicine, Kameda Medical Center, Kamogawa, Japan
| | - Ricard Ferrer
- Department of Intensive Care, Department of Medicine, SODIR Research Group, VHIR, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Massimo Girardis
- Anesthesia and Intensive Care Department, University Hospital of Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Marc Leone
- Department of Anesthesiology and Intensive Care Unit, Nord Hospital, Aix Marseille University, Assistance Publique Hôpitaux Universitaires de Marseille, Marseille, France
| | - Gennaro DePascale
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A, Gemelli IRCCS, Rome, Italy
| | - Peter Pickkers
- Department of Intensive Care Medicine, Radboud UMC Nijmegen, Nijmegen, The Netherlands
| | - Pierre Tissieres
- Pediatric Intensive Care and Neonatal Medicine, Bicêtre Hospital, AP-HP Paris Saclay University, Le Kremlin-Bicêtre, Paris, France
| | - Filippo Annoni
- Department of Intensive Care, Erasme University Hospital, Université Libre de Buxelles, Brussels, Belgium
| | - Katarzyna Kotfis
- Department of Anaesthesiology, Intensive Therapy and Pain Medicine, Pomeranian Medical University, Szczecin, Poland
| | - Giovanni Landoni
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Münster, Albert-Schweitzer Campus 1, Building A1, 48149, Münster, Germany
| | - Patrick M Wieruszewski
- Department of Pharmacy, Mayo Clinic, Rochester, MN, USA
- Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA
| | - Daniel De Backer
- Department of Intensive Care, CHIREC Hospitals, Université Libre de Bruxelles, Brussels, Belgium
| | - Jean-Louis Vincent
- Department of Intensive Care, Erasme University Hospital, Université Libre de Buxelles, Brussels, Belgium
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Hospital, Melbourne, Australia
- Department of Critical Care, The University of Melbourne, Melbourne, Australia
- Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia
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Xourgia E, Exadaktylos AK, Chalkias A, Ziaka M. ANGIOTENSIN II IN THE TREATMENT OF DISTRIBUTIVE SHOCK: A SYSTEMATIC-REVIEW AND META-ANALYSIS. Shock 2024; 62:155-164. [PMID: 38888542 DOI: 10.1097/shk.0000000000002384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
ABSTRACT Objective: While nonnorepinephrine vasopressors are increasingly used as a rescue therapy in cases of norepinephrine-refractory shock, data on their efficacy are limited. This systematic review and meta-analysis aims to synthesize existing literature on the efficacy of angiotensin II (ATII) in distributive shock. Methods: We preregistered our meta-analysis with PROSPERO (CRD42023456136). We searched PubMed, Scopus, and gray literature for studies presenting outcomes on ATII use in distributive shock. The primary outcome of the meta-analysis was all-cause mortality. We used a random effects model to calculate pooled risk ratio (RR) and 95% confidence intervals (CIs). Results: By incorporating data from 1,555 patients included in 10 studies, we found that however, all-cause mortality was similar among patients receiving ATII and controls (RR = 1.02; 95% CI: 0.89 to 1.16, P = 0.81), the reduction in norepinephrine or norepinephrine-equivalent dose at 3 h after treatment initiation was greater among patients receiving ATII (MD = -0.06; 95% CI: -0.11 to -0.02, P = 0.008), while there were no higher rates of adverse events reported among ATII patients. Conclusions: While ATII did not reduce mortality among distributive shock patients, it allowed for significant adjunctive vasopressor reduction at 3 h without an increase in reported adverse events, deeming it a viable alternative for the increasingly adopted multimodal vasopressor for minimizing catecholamine exposure and its adverse events.
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Affiliation(s)
| | - Aristomenis K Exadaktylos
- Department of Emergency Medicine, Inselspital, University Hospital, University of Bern, Bern, Switzerland
| | | | - Mairi Ziaka
- Department of Emergency Medicine, Inselspital, University Hospital, University of Bern, Bern, Switzerland
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6
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Picod A, Garcia B, Van Lier D, Pickkers P, Herpain A, Mebazaa A, Azibani F. Impaired angiotensin II signaling in septic shock. Ann Intensive Care 2024; 14:89. [PMID: 38877367 PMCID: PMC11178728 DOI: 10.1186/s13613-024-01325-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 05/29/2024] [Indexed: 06/16/2024] Open
Abstract
Recent years have seen a resurgence of interest for the renin-angiotensin-aldosterone system in critically ill patients. Emerging data suggest that this vital homeostatic system, which plays a crucial role in maintaining systemic and renal hemodynamics during stressful conditions, is altered in septic shock, ultimately leading to impaired angiotensin II-angiotensin II type 1 receptor signaling. Indeed, available evidence from both experimental models and human studies indicates that alterations in the renin-angiotensin-aldosterone system during septic shock can occur at three distinct levels: 1. Impaired generation of angiotensin II, possibly attributable to defects in angiotensin-converting enzyme activity; 2. Enhanced degradation of angiotensin II by peptidases; and/or 3. Unavailability of angiotensin II type 1 receptor due to internalization or reduced synthesis. These alterations can occur either independently or in combination, ultimately leading to an uncoupling between the renin-angiotensin-aldosterone system input and downstream angiotensin II type 1 receptor signaling. It remains unclear whether exogenous angiotensin II infusion can adequately address all these mechanisms, and additional interventions may be required. These observations open a new avenue of research and offer the potential for novel therapeutic strategies to improve patient prognosis. In the near future, a deeper understanding of renin-angiotensin-aldosterone system alterations in septic shock should help to decipher patients' phenotypes and to implement targeted interventions.
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Affiliation(s)
- Adrien Picod
- INSERM, UMR-S 942 MASCOT-Université Paris-Cité, Paris, France.
| | - Bruno Garcia
- Department of Intensive Care Medicine, Centre Hospitalier Universitaire de Lille, Lille, France
- Experimental Laboratory of Intensive Care, Université Libre de Bruxelles, Brussels, Belgium
| | - Dirk Van Lier
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Peter Pickkers
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Antoine Herpain
- Experimental Laboratory of Intensive Care, Université Libre de Bruxelles, Brussels, Belgium
- Department of Intensive Care Medicine, St. Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Alexandre Mebazaa
- INSERM, UMR-S 942 MASCOT-Université Paris-Cité, Paris, France
- Department of Anesthesiology, Burns and Critical Care, Hopitaux Saint-Louis-Lariboisière, AP-HP, Paris, France
| | - Feriel Azibani
- INSERM, UMR-S 942 MASCOT-Université Paris-Cité, Paris, France
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Schaich CL, Leisman DE, Goldberg MB, Filbin MR, Khanna AK, Chappell MC. Dysfunction of the renin-angiotensin-aldosterone system in human septic shock. Peptides 2024; 176:171201. [PMID: 38555976 PMCID: PMC11060897 DOI: 10.1016/j.peptides.2024.171201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/20/2024] [Accepted: 03/27/2024] [Indexed: 04/02/2024]
Abstract
Sepsis and septic shock are global healthcare problems associated with mortality rates of up to 40% despite optimal standard-of-care therapy and constitute the primary cause of death in intensive care units worldwide. Circulating biomarkers of septic shock severity may represent a clinically relevant approach to individualize those patients at risk for worse outcomes early in the course of the disease, which may facilitate early and more precise interventions to improve the clinical course. However, currently used septic shock biomarkers, including lactate, may be non-specific and have variable impact on prognosis and/or disease management. Activation of the renin-angiotensin-aldosterone system (RAAS) is likely an early event in septic shock, and studies suggest that an elevated level of renin, the early and committed step in the RAAS cascade, is a better predictor of worse outcomes in septic shock, including mortality, than the current standard-of-care measure of lactate. Despite a robust increase in renin, other elements of the RAAS, including endogenous levels of Ang II, may fail to sufficiently increase to maintain blood pressure, tissue perfusion, and protective immune responses in septic shock patients. We review the current clinical literature regarding the dysfunction of the RAAS in septic shock and potential therapeutic approaches to improve clinical outcomes.
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Affiliation(s)
- Christopher L Schaich
- Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Daniel E Leisman
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Marcia B Goldberg
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Micheal R Filbin
- Department of Emergency Medicine, Massachusetts General Hospital,Boston, MA, USA
| | - Ashish K Khanna
- Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Department of Anesthesiology, Section on Critical Care Medicine, Atrium Health Wake Forest Baptist Medical Center, USA; Outcomes Research Consortium, Cleveland, OH, USA
| | - Mark C Chappell
- Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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Kotani Y, Belletti A, Maiucci G, Lodovici M, Fresilli S, Landoni G, Bellomo R, Zarbock A. Renin as a Prognostic Marker in Intensive Care and Perioperative Settings: A Scoping Review. Anesth Analg 2024; 138:929-936. [PMID: 38358109 DOI: 10.1213/ane.0000000000006682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
Serum renin increases in response to sympathetic nerve activation and hypotension. Recent studies have reported the association of serum renin levels with adverse clinical outcomes in acute care settings. This scoping review aimed to systematically review the available literature on renin as a prognostic marker in intensive care and perioperative patients. We searched for studies published since inception until March 31, 2023, which assessed the association between serum renin levels and clinical outcomes or the effect of synthetic angiotensin II administration on serum renin levels in critically ill and perioperative patients in PubMed, Embase, and the Cochrane Library. The primary outcome was mortality at the longest follow-up; the secondary outcomes were adverse renal outcomes (ie, acute kidney injury, the need for renal replacement therapy, and major adverse kidney events), hemodynamic instability, outcomes to angiotensin II administration, and prognostic performance for mortality when compared with lactate. Among the 2081 studies identified, we included 16 studies with 1573 patients (7 studies on shock, 5 on nonspecific critical illness, 2 on cardiac surgery, 1 on noncardiac surgery, and 1 on coronavirus disease 2019). A significant association between serum renin levels and poor outcomes was identified in 14 studies, with 10 studies demonstrating an association with mortality. One post hoc analysis found that angiotensin II administration reduced mortality in patients with markedly elevated renin values. Two studies showed that renin was superior to lactate as a prognostic marker of mortality. Our scoping review showed that elevated serum renin levels may be associated with clinically relevant outcomes among various perioperative and intensive care populations. Increased serum renin levels may identify patients in which synthetic angiotensin II administration improves clinical outcomes and may outperform serum lactate in predicting mortality.
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Affiliation(s)
- Yuki Kotani
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
- Department of Intensive Care Medicine, Kameda Medical Center, Kamogawa, Japan
| | - Alessandro Belletti
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giacomo Maiucci
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Martina Lodovici
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Fresilli
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giovanni Landoni
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Rinaldo Bellomo
- Department of Critical Care, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Critical Care, Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, Muenster, Germany
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9
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Manson DK, Dzierba AL, Seitz KM, Brodie D. Reply to: Rethinking Vasopressor Education: The Need to Avoid Teaching the Bare Minimum. ATS Sch 2023; 4:391-392. [PMID: 37795114 PMCID: PMC10547031 DOI: 10.34197/ats-scholar.2023-0049le] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023] Open
Affiliation(s)
| | - Amy L. Dzierba
- Department of Pharmacy, NewYork-Presbyterian Hospital, Columbia University Irving Medical Center, New York, New York
| | - Kaitlin M. Seitz
- Division of Pulmonary and Critical Care Medicine, NewYork-Presbyterian Hospital, Weill Cornell Medical Center, New York, New York; and
| | - Daniel Brodie
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medicine, Baltimore, Maryland
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Semedi BP, Rehatta NM, Soetjipto S, Nugraha J, Mahyuddin MH, Arnindita JN, Wairooy NAP. How Effective is Angiotensin II in Decreasing Mortality of Vasodilatory Shock? A Systematic Review. Open Access Emerg Med 2023; 15:1-11. [PMID: 36636460 PMCID: PMC9830054 DOI: 10.2147/oaem.s391167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 12/20/2022] [Indexed: 01/05/2023] Open
Abstract
Background Patients with severe vasodilation accompanied by refractory hypotension despite high doses of vasopressors were associated with a high mortality rate. The Ang-2 for the Treatment of High-Output Shock (ATHOS) 3 trial demonstrated that angiotensin 2 (Ang-2) could effectively increase MAP and blood pressure in vasodilatory shock patients. This systematic review aims to summarize the impact of Ang-2 for the treatment of vasodilatory shock on clinical outcomes, including length of stay, MAP level (before and after), and mortality also Ang-2 dose needed. Methods A systematic search in PubMed, Sage, ScienceDirect, Scopus and Gray literature was conducted to obtain studies about the use of Ang-2 in vasodilatory shock patients. Results In all of the studies that we obtained, there were different results regarding mortality in patients with vasodilatory shock with Ang-2. Mortality was significantly lower when Ang-2 was administered to patients with elevated renin. The initial dose of Ang-2 can be started at 10-20 ng/kg/min, but there is no agreement on the maximum dose. Ang-2 may be considered a third-line vasopressor if the targeted MAP has not been achieved after administration of norepinephrine >200 ng/kg/min for more than 6 hours. Although not statistically significant, the use of Ang-2 can reduce the length of stay in the ICU and in the hospital when compared to patients without Ang-2 therapy, in addition to reducing the dose of vasopressor. Conclusion Overall, the use of Ang-2 has potential to be a regimen for patients with vasodilatory shock. Further study is needed to obtain more data.
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Affiliation(s)
- Bambang Pujo Semedi
- Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, East Java, 60132, Indonesia,Department of Anesthesiology and Reanimation, Medical Faculty of Medicine, Universitas Airlangga—Dr Soetomo General Hospital, Surabaya, East Java, 60132, Indonesia
| | - Nancy Margarita Rehatta
- Department of Anesthesiology and Reanimation, Medical Faculty of Medicine, Universitas Airlangga—Dr Soetomo General Hospital, Surabaya, East Java, 60132, Indonesia,Correspondence: Nancy Margarita Rehatta, Email
| | - Soetjipto Soetjipto
- Department of Medical Biochemistry, Medical Faculty of Universitas Airlangga, Surabaya, East Java, 60132, Indonesia
| | - Jusak Nugraha
- Department of Clinical Pathology, Medical Faculty of Universitas Airlangga, Surabaya, East Java, 60132, Indonesia
| | | | | | - Nabilah A P Wairooy
- Medical Faculty Universitas Airlangga, Surabaya, East Java, 60132, Indonesia
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11
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Renin as a Marker of Tissue Perfusion, Septic Shock and Mortality in Septic Patients: A Prospective Observational Study. Int J Mol Sci 2022; 23:ijms23169133. [PMID: 36012398 PMCID: PMC9409106 DOI: 10.3390/ijms23169133] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
Sepsis is a life-threatening organ dysfunction caused by the dysregulation of the host’s response to an infection, where the dominant mechanism is tissue hypoperfusion. Currently, the marker used to define tissue disorders is lactate levels, which may be elevated in other disease states as well. Renin is an essential hormone for the proper functioning of the renin-angiotensin-aldosterone (RASS) system. It is secreted in the glomerular apparatus in response to hypoperfusion. This study aimed to assess the usefulness of renin as a marker of tissue hypoperfusion in patients with sepsis and septic shock. A final group of 48 patients treated for sepsis and septic shock in the intensive care unit was included. Blood samples for renin quantification were collected in the morning as a part of routine blood analysis on the first, third, and fifth days. Sepsis was diagnosed in 19 patients (39.6%), and septic shock was diagnosed in 29 patients (60.4%). There was no significant difference in renin concentration between patients who received and did not receive continuous renal replacement therapy (CRRT) on any study day. Therefore, all samples were analyzed together in subsequent analyses. There was a significant difference in renin concentration between sepsis survivors and non-survivors on the third (31.5 and 119.9 pg/mL, respectively) and fifth (18.2 and 106.7 pg/mL, respectively) days. As a survival marker, renin was characterized by 69% and 71% overall accuracy if determined on the third and fifth days, respectively. There was a significant difference in renin concentration between sepsis and septic shock patients on the first (45.8 and 103.4 pg/mL, respectively) and third (24.7 and 102.1 pg/mL, respectively) days. At an optimal cut-off of 87 pg/mL, renin had very good specificity and a positive likelihood ratio. Renin was a strong predictor of mortality in patients with sepsis and septic shock. Further, the level of renin in patients with septic shock was significantly higher than in patients with sepsis. In combination with the assessment of lactate concentration, renin seems to be the optimal parameter for monitoring tissue hypoperfusion and could be helpful for septic shock diagnosis, as well as for identifying candidate patients for CRRT.
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12
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Jozwiak M. Alternatives to norepinephrine in septic shock: Which agents and when? JOURNAL OF INTENSIVE MEDICINE 2022; 2:223-232. [PMID: 36788938 PMCID: PMC9924015 DOI: 10.1016/j.jointm.2022.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/28/2022] [Accepted: 05/07/2022] [Indexed: 10/18/2022]
Abstract
Vasopressors are the cornerstone of hemodynamic management in patients with septic shock. Norepinephrine is currently recommended as the first-line vasopressor in these patients. In addition to norepinephrine, there are many other potent vasopressors with specific properties and/or advantages that act on vessels through different pathways after activation of specific receptors; these could be of interest in patients with septic shock. Dopamine is no longer recommended in patients with septic shock because its use is associated with a higher rate of cardiac arrhythmias without any benefit in terms of mortality or organ dysfunction. Epinephrine is currently considered as a second-line vasopressor therapy, because of the higher rate of associated metabolic and cardiac adverse effects compared with norepinephrine; however, it may be considered in settings where norepinephrine is unavailable or in patients with refractory septic shock and myocardial dysfunction. Owing to its potential effects on mortality and renal function and its norepinephrine-sparing effect, vasopressin is recommended as second-line vasopressor therapy instead of norepinephrine dose escalation in patients with septic shock and persistent arterial hypotension. However, two synthetic analogs of vasopressin, namely, terlipressin and selepressin, have not yet been employed in the management of patients with septic shock, as their use is associated with a higher rate of digital ischemia. Finally, angiotensin Ⅱ also appears to be a promising vasopressor in patients with septic shock, especially in the most severe cases and/or in patients with acute kidney injury requiring renal replacement therapy. Nevertheless, due to limited evidence and concerns regarding safety (which remains unclear because of potential adverse effects related to its marked vasopressor activity), angiotensin Ⅱ is currently not recommended in patients with septic shock. Further studies are needed to better define the role of these vasopressors in the management of these patients.
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Affiliation(s)
- Mathieu Jozwiak
- Service de Médecine Intensive Réanimation, Centre Hospitalier Universitaire l'Archet 1, 151 route Saint Antoine de Ginestière, 06200 Nice, France,Equipe 2 CARRES UR2CA – Unité de Recherche Clinique Côte d'Azur, Université Côte d'Azur UCA, 06103 Nice, France
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13
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Leisman DE, Mehta A, Thompson BT, Charland NC, Gonye ALK, Gushterova I, Kays KR, Khanna HK, LaSalle TJ, Lavin-Parsons KM, Lilley BM, Lodenstein CL, Manakongtreecheep K, Margolin JD, McKaig BN, Rojas-Lopez M, Russo BC, Sharma N, Tantivit J, Thomas MF, Parry BA, Villani AC, Sade-Feldman M, Hacohen N, Filbin MR, Goldberg MB. Alveolar, Endothelial, and Organ Injury Marker Dynamics in Severe COVID-19. Am J Respir Crit Care Med 2022; 205:507-519. [PMID: 34878969 PMCID: PMC8906476 DOI: 10.1164/rccm.202106-1514oc] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 12/07/2021] [Indexed: 11/23/2022] Open
Abstract
Rationale: Alveolar and endothelial injury may be differentially associated with coronavirus disease (COVID-19) severity over time. Objectives: To describe alveolar and endothelial injury dynamics and associations with COVID-19 severity, cardiorenovascular injury, and outcomes. Methods: This single-center observational study enrolled patients with COVID-19 requiring respiratory support at emergency department presentation. More than 40 markers of alveolar (including receptor for advanced glycation endproducts [RAGE]), endothelial (including angiopoietin-2), and cardiorenovascular injury (including renin, kidney injury molecule-1, and troponin-I) were serially compared between invasively and spontaneously ventilated patients using mixed-effects repeated-measures models. Ventilatory ratios were calculated for intubated patients. Associations of biomarkers with modified World Health Organization scale at Day 28 were determined with multivariable proportional-odds regression. Measurements and Main Results: Of 225 patients, 74 (33%) received invasive ventilation at Day 0. RAGE was 1.80-fold higher in invasive ventilation patients at Day 0 (95% confidence interval [CI], 1.50-2.17) versus spontaneous ventilation, but decreased over time in all patients. Changes in alveolar markers did not correlate with changes in endothelial, cardiac, or renal injury markers. In contrast, endothelial markers were similar to lower at Day 0 for invasive ventilation versus spontaneous ventilation, but then increased over time only among intubated patients. In intubated patients, angiopoietin-2 was similar (fold difference, 1.02; 95% CI, 0.89-1.17) to nonintubated patients at Day 0 but 1.80-fold higher (95% CI, 1.56-2.06) at Day 3; cardiorenovascular injury markers showed similar patterns. Endothelial markers were not consistently associated with ventilatory ratios. Endothelial markers were more often significantly associated with 28-day outcomes than alveolar markers. Conclusions: Alveolar injury markers increase early. Endothelial injury markers increase later and are associated with cardiorenovascular injury and 28-day outcome. Alveolar and endothelial injury likely contribute at different times to disease progression in severe COVID-19.
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Affiliation(s)
- Daniel E. Leisman
- Department of Anesthesiology, Critical Care, and Pain Medicine
- Department of Medicine
| | - Arnav Mehta
- Massachusetts General Hospital Cancer Center
- Department of Medicine
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | | | - Anna L. K. Gonye
- Center for Cancer Research
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
| | - Irena Gushterova
- Center for Cancer Research
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
| | | | | | - Thomas J. LaSalle
- Center for Cancer Research
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
| | | | | | | | - Kasidet Manakongtreecheep
- Center for Cancer Research
- Center for Immunology and Inflammatory Diseases, and
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
| | | | | | - Maricarmen Rojas-Lopez
- Center for Bacterial Pathogenesis, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- Department of Medicine
- Department of Microbiology, and
| | - Brian C. Russo
- Center for Bacterial Pathogenesis, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- Department of Medicine
- Department of Microbiology, and
| | - Nihaarika Sharma
- Center for Cancer Research
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
| | - Jessica Tantivit
- Center for Cancer Research
- Center for Immunology and Inflammatory Diseases, and
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
| | - Molly F. Thomas
- Center for Cancer Research
- Center for Immunology and Inflammatory Diseases, and
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
| | | | - Alexandra-Chloé Villani
- Massachusetts General Hospital Cancer Center
- Department of Medicine
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
| | - Moshe Sade-Feldman
- Massachusetts General Hospital Cancer Center
- Department of Medicine
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
| | - Nir Hacohen
- Massachusetts General Hospital Cancer Center
- Department of Medicine
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
| | - Michael R. Filbin
- Department of Emergency Medicine, and
- Department of Emergency Medicine, Harvard Medical School, Boston, Massachusetts
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
| | - Marcia B. Goldberg
- Center for Bacterial Pathogenesis, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- Department of Medicine
- Department of Microbiology, and
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; and
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14
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Roe T, Welbourne J, Nikitas N. Endocrine dysregulation in aneurysmal subarachnoid haemorrhage. Br J Neurosurg 2022; 36:358-367. [PMID: 35170377 DOI: 10.1080/02688697.2022.2039378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
INTRODUCTION Aneurysmal Subarachnoid haemorrhage (aSAH) is one of the most common causes of neurocritical care admission. Consistent evidence has been suggestive of endocrine dysregulation in aSAH. This review aims to provide an up-to-date presentation of the available evidence regarding endocrine dysregulation in aneurysmal subarachnoid haemorrhage. METHODS A comprehensive literature search was performed using PubMed database. All available evidence related to endocrine dysregulation in hypothalamic-pituitary hormones, adrenal hormones and natriuretic peptides after aSAH, published since 2010, were reviewed. RESULTS There have been reports of varying prevalence of dysregulation in hypothalamic-pituitary and adrenal hormones in aSAH. The cause of this dysregulation and its pattern remain unclear. Hypothalamic-pituitary and adrenal dysregulation have been associated with higher incidence of poor neurological outcome and increased mortality. Whilst there is evidence that long-term dysregulation of these axes may also develop, it appears to be less frequent than the acute-phase dysregulation and transient in pattern. Increased levels of catecholamines have been reported in the hyper-acute phase of aSAH with reported inconsistent correlation with the outcomes and the complications of the disease. There is growing evidence that of a causal link between the endocrine dysregulation and the development of hyponatraemia and delayed cerebral ischaemia, in the acute phase of aSAH. However, the pathophysiological mechanism and pattern of endocrine dysregulation which could be causally associated with these complications still remain debatable. CONCLUSION The evidence, mainly from small observational and heterogeneous in methodology studies, is suggestive of adverse effects of the endocrine dysregulation on the outcome and the incidence of complications of the disease. However, the cause of this dysregulation and a pathophysiological mechanism that could link its presence with the development of acute complications and the outcome of the aSAH remain unclear. Further research is warranted to elucidate the clinical significance of endocrine dysregulation in subarachnoid haemorrhage.
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Affiliation(s)
- Thomas Roe
- Department of Intensive Care Medicine, Derriford Hospital, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Jessie Welbourne
- Department of Intensive Care Medicine, Derriford Hospital, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Nikitas Nikitas
- Department of Intensive Care Medicine, Derriford Hospital, University Hospitals Plymouth NHS Trust, Plymouth, UK
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15
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Laghlam D, Jozwiak M, Nguyen LS. Renin-Angiotensin-Aldosterone System and Immunomodulation: A State-of-the-Art Review. Cells 2021; 10:cells10071767. [PMID: 34359936 PMCID: PMC8303450 DOI: 10.3390/cells10071767] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/30/2021] [Accepted: 07/09/2021] [Indexed: 12/11/2022] Open
Abstract
The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.
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16
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Vassiliou AG, Athanasiou N, Vassiliadi DA, Jahaj E, Keskinidou C, Kotanidou A, Dimopoulou I. Glucocorticoid and mineralocorticoid receptor expression in critical illness: A narrative review. World J Crit Care Med 2021; 10:102-111. [PMID: 34316445 PMCID: PMC8291002 DOI: 10.5492/wjccm.v10.i4.102] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/18/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
The glucocorticoid receptor (GCR) and the mineralocorticoid receptor (MR) are members of the steroid receptor superfamily of hormone-dependent transcription factors. The receptors are structurally and functionally related. They are localized in the cytosol and translocate into the nucleus after ligand binding. GCRs and MRs can be co-expressed within the same cell, and it is believed that the balance in GCR and MR expression is crucial for homeostasis and plays a key role in normal adaptation. In critical illness, the hypothalamic-pituitary-adrenal axis is activated, and as a consequence, serum cortisol concentrations are high. However, a number of patients exhibit relatively low cortisol levels for the degree of illness severity. Glucocorticoid (GC) actions are facilitated by GCR, whose dysfunction leads to GC tissue resistance. The MR is unique in this family in that it binds to both aldosterone and cortisol. Endogenous GCs play a critical role in controlling inflammatory responses in critical illness. Intracellular GC concentrations can differ greatly from blood levels due to the action of the two 11β-hydroxysteroid dehydrogenase isozymes, type 1 and type 2. 11β-hydroxysteroid dehydrogenases interconvert endogenous active cortisol and intrinsically inert cortisone. The degree of expression of the two isozymes has the potential to dramatically influence local GC availability within cells and tissues. In this review, we will explore the clinical studies that aimed to elucidate the role of MR and GCR expression in the inflammatory response seen in critical illness.
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Affiliation(s)
- Alice G Vassiliou
- 1st Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens, “Evangelismos” Hospital, Athens 10676, Greece
| | - Nikolaos Athanasiou
- 1st Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens, “Evangelismos” Hospital, Athens 10676, Greece
| | - Dimitra A Vassiliadi
- Department of Endocrinology, Diabetes and Metabolism, “Evangelismos” Hospital, Athens 10676, Greece
| | - Edison Jahaj
- 1st Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens, “Evangelismos” Hospital, Athens 10676, Greece
| | - Chrysi Keskinidou
- 1st Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens, “Evangelismos” Hospital, Athens 10676, Greece
| | - Anastasia Kotanidou
- 1st Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens, “Evangelismos” Hospital, Athens 10676, Greece
| | - Ioanna Dimopoulou
- 1st Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens, “Evangelismos” Hospital, Athens 10676, Greece
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17
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Chen DN, Du J, Xie Y, Li M, Wang RL, Tian R. Relationship between early serum sodium and potassium levels and AKI severity and prognosis in oliguric AKI patients. Int Urol Nephrol 2021; 53:1171-1187. [PMID: 33389512 DOI: 10.1007/s11255-020-02724-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/16/2020] [Indexed: 12/28/2022]
Abstract
PURPOSE Acute kidney injury (AKI) is a common organ dysfunction in ICU and up to now there is no good way to predict the AKI progression and patient prognosis. Blood electrolyte tests are common in ICU, but there are few studies on early blood electrolytes and the AKI progression and patient prognosis. Therefore, we concentrated on the serum sodium and potassium levels before AKI diagnosis and evaluated the relationship between serum sodium and potassium levels and the severity and prognosis of AKI. METHODS This study included data of all patients from the MIMIC-III. We used the urine output criteria in the KDIGO as diagnostic criteria for oliguric AKI. Patients admitted to the ICU several times only included their initial ICU admission results. Patients younger than 18 years old, diagnosed with AKI stage 3, ICU stays less than 24 h or without corresponding laboratory results or data were excluded. The included patients were divided into four groups based on the interquartile range of serum sodium and potassium. We evaluated the serum sodium and potassium levels before AKI diagnosis and AKI severity and prognosis through retrospective analysis. RESULTS Patients with serum potassium > 4.6 mmol/L were more likely to progress to AKI stage 3 or death than patients with serum potassium ≤ 4.6 mmol/L (overall p < 0.0001). Patients with sodium < 137 mmol/L or > 141 mmol/L had a higher risk of progressing to AKI stage 3 (overall p = 0.00023) and risk of death (overall p < 0.0001) than other patients. In the Cox regression model, after adjusting for age, sex, and BMI, serum sodium or potassium were associated with AKI progression and prognosis (p < 0.01). After continuing to adjust for comorbidities, serum potassium was still associated with AKI progression and prognosis (p < 0.01), but serum sodium was only associated with prognosis (p = 0.027). After adjusting for other indicators, there was no statistically significant correlation between serum sodium or potassium and AKI progression and prognosis. After adjusting for serum sodium or potassium, the corresponding results were not significantly different from those before adjustment. CONCLUSION This study found that abnormal serum sodium or potassium levels before AKI diagnosis were more likely to lead to AKI progression and poor prognosis, of which lower serum sodium and higher serum potassium were more likely to progress to AKI stage 3 or death.
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Affiliation(s)
- Dao-Nan Chen
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 201620, China
| | - Jiang Du
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 201620, China
| | - Yun Xie
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 201620, China
| | - Ming Li
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 201620, China
| | - Rui-Lan Wang
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 201620, China
| | - Rui Tian
- Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 201620, China.
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18
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Use of Angiotensin II in Severe Vasoplegia After Left Pneumonectomy Requiring Cardiopulmonary Bypass: A Renin Response Analysis. Crit Care Med 2021; 48:e912-e915. [PMID: 32931196 DOI: 10.1097/ccm.0000000000004502] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Describe a case of post-pneumonectomy vasoplegia managed with angiotensin II. Plasma renin activity was measured at specific time intervals to describe the relationship between endogenous renin activity and exogenous angiotensin II supplementation. DESIGN Case report. SETTING Spectrum Health Cardiothoracic Critical Care Unit. PATIENTS Fifty-seven-year-old male. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Plasma renin activity at five pre-determined time points. Angiotensin II caused a significant increase in mean arterial pressure and a rapid reduction in catecholamine vasopressor doses from 0.75 to 0.31 mcg/kg/min norepinephrine equivalents. Plasma renin activity drawn immediately before angiotensin II initiation was 40 ng/mL/hr (normal, 0.6-3.0 ng/mL/hr) with resultant drop to 22 and 12 ng/mL/hr at 2 and 6 hours after angiotensin II initiation, respectively. The patient suffered no end-organ damage and achieved a positive outcome, discharging home on postoperative day 11. CONCLUSION Exogenous angiotensin II reduced catecholamine vasopressor doses and had an apparent effect in reducing endogenous renin production in this case. Prospective research is warranted to determine the utility of angiotensin II and to better understand it effects on the dysfunctional renin-angiotensin-aldosterone system during vasoplegic shock.
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Fernandes D, Pacheco LK, Sordi R, Scheschowitsch K, Ramos GC, Assreuy J. Angiotensin II receptor type 1 blockade improves hyporesponsiveness to vasopressors in septic shock. Eur J Pharmacol 2021; 897:173953. [PMID: 33617825 DOI: 10.1016/j.ejphar.2021.173953] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 02/04/2021] [Accepted: 02/15/2021] [Indexed: 11/30/2022]
Abstract
Sepsis activates the renin-angiotensin system and the production of angiotensin II, which has a key role in the regulation of blood pressure through AT1 receptors. However, excessive activation of AT1 receptor is associated with deleterious effects. We investigated the consequences of a differential blockade of AT1 receptor caused by two doses of losartan (0.25 mg/kg or 15 mg/kg, s.c), a selective AT1 receptor antagonist on sepsis outcome. These doses reduced the effect of angiotensin II in normal rats by 30% and >90% 8 h after administration, respectively, but only the higher dose maintained its inhibitory effect (~70%) 24 h after injection. Sepsis was induced by cecal ligation and puncture (CLP). Losartan was injected 2 h after CLP and parameters were evaluated 6 and 24 h after CLP. Septic rats developed hypotension and hyporesponsiveness to vasoconstrictors, an intense inflammatory process and increase in plasma markers of organ dysfunction. The lower dose of losartan improved the vasoconstrictive response to phenylephrine and angiotensin II, reduced lung myeloperoxidase and prevented leukopenia 24 h after CLP, but it did not reduce NOS-2 expression, plasma IL-6 levels or organ injury parameters of septic rats. On the other hand, the higher dose of losartan worsened the response to vasoconstrictors, potentiated the hypotension and increased further levels of creatine, urea and lactate in septic rats. Therefore, an early and partial blockade of AT1 receptor with a low dose of losartan may counteract sepsis-induced refractoriness to vasoconstrictors thus providing an opportunity to improve the outcome of this condition.
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MESH Headings
- Angiotensin II/metabolism
- Angiotensin II Type 1 Receptor Blockers/pharmacology
- Animals
- Arterial Pressure/drug effects
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Female
- Hypotension/drug therapy
- Hypotension/metabolism
- Hypotension/microbiology
- Hypotension/physiopathology
- Inflammation Mediators/blood
- Losartan/pharmacology
- Rats, Wistar
- Receptor, Angiotensin, Type 2/drug effects
- Receptor, Angiotensin, Type 2/metabolism
- Renin-Angiotensin System/drug effects
- Shock, Septic/drug therapy
- Shock, Septic/metabolism
- Shock, Septic/microbiology
- Shock, Septic/physiopathology
- Vasoconstriction/drug effects
- Vasoconstrictor Agents/pharmacology
- Rats
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Affiliation(s)
- Daniel Fernandes
- Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Letícia Kramer Pacheco
- Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Regina Sordi
- Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Karin Scheschowitsch
- Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Gustavo Campos Ramos
- Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Jamil Assreuy
- Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
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20
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Lee HW, Suh JK, Jang E, Lee SM. Effect of angiotensin converting enzyme inhibitor and angiotensin II receptor blocker on the patients with sepsis. Korean J Intern Med 2021; 36:371-381. [PMID: 32264653 PMCID: PMC7969078 DOI: 10.3904/kjim.2019.262] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 11/25/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/AIMS Inhibitors of the renin-angiotensin system, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), reportedly have anti-inflammatory effects. This study assessed the association of prior use of ACE inhibitors and ARBs with sepsis-related clinical outcomes. METHODS A population-based observational study was conducted using the Health Insurance Review and Assessment Service claims data. Among the adult patients hospitalized with new onset of sepsis in 2012, patients who took ARBs or ACE inhibitors at least 30 days prior to hospitalization were analyzed. Generalized linear models and logistic regression were used to examine the relation between the prior use of medication and clinical outcomes, such as in-hospital mortality, mechanical ventilation, and length of stay. RESULTS Of a total of 27,628 patients who were hospitalized for sepsis, the ACE inhibitor, ARB, and non-user groups included 1,214 (4.4%), 3,951 (14.4%), and 22,463 (82.1%) patients, respectively. As the patients in the ACE inhibitor and ARB groups had several comorbid conditions, higher rates of intensive care unit admission, hemodialysis, and mechanical ventilation were observed. However, after covariate adjustment, the use of ACE inhibitor (odds ratio [OR], 0.752; 95% confidence interval [CI], 0.661 to 0.855) or ARB (OR, 0.575; 95% CI, 0.532 to 0.621) was significantly associated with a lower rate of in-hospital mortality. CONCLUSION Pre-hospitalization use of ACE inhibitors or ARBs for sepsis was an independent factor for a lower rate of in-hospital mortality.
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Affiliation(s)
- Hyun Woo Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Jae Kyung Suh
- National Evidence-Based Healthcare Collaborating Agency, Seoul, Korea
| | - Eunjin Jang
- Department of Information Statistics, Andong National University, Andong, Korea
| | - Sang-Min Lee
- National Evidence-Based Healthcare Collaborating Agency, Seoul, Korea
- Correspondence to Sang-Min Lee, Ph.D. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-0833 Fax: +82-2-764-2199 E-mail:
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21
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Raj J, Sanchez Lara A, Bell R, Tappin S. Canine isolated hypoaldosteronism. VETERINARY RECORD CASE REPORTS 2021. [DOI: 10.1002/vrc2.29] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Jennifer Raj
- Small Animal Internal Medicine Dick White Referrals Ltd Six Mile Bottom Cambridgeshire UK
| | | | - Rory Bell
- Small Animal Internal Medicine Dick White Referrals Ltd Six Mile Bottom Cambridgeshire UK
| | - Simon Tappin
- Small Animal Internal Medicine Dick White Referrals Ltd Six Mile Bottom Cambridgeshire UK
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22
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Bellomo R, Forni LG, Busse LW, McCurdy MT, Ham KR, Boldt DW, Hästbacka J, Khanna AK, Albertson TE, Tumlin J, Storey K, Handisides D, Tidmarsh GF, Chawla LS, Ostermann M. Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial. Am J Respir Crit Care Med 2020; 202:1253-1261. [PMID: 32609011 PMCID: PMC7605187 DOI: 10.1164/rccm.201911-2172oc] [Citation(s) in RCA: 132] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy. Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS. Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours. Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13–58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios (r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo (P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) (P = 0.048 for the interaction). Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 02338843).
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Affiliation(s)
- Rinaldo Bellomo
- Centre for Integrated Critical Care, Department of Medicine & Radiology, The University of Melbourne, Melbourne, Victoria, Australia.,Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Lui G Forni
- Intensive Care Unit, Royal Surrey Hospital Foundation Trust, Guildford, United Kingdom.,Department of Clinical & Experimental Medicine, School of Biosciences & Medicine, University of Surrey, Guildford, United Kingdom
| | - Laurence W Busse
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, and
| | - Michael T McCurdy
- Division of Pulmonary & Critical Care Medicine, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Kealy R Ham
- Department of Critical Care, Regions Hospital, University of Minnesota, St. Paul, Minnesota
| | - David W Boldt
- Division of Critical Care, Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, California
| | - Johanna Hästbacka
- Division of Intensive Care Medicine, Department of Perioperative, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Ashish K Khanna
- Department of Anesthesiology, Section on Critical Care Medicine, School of Medicine, Wake Forest University, Winston-Salem, North Carolina.,Outcomes Research Consortium, Cleveland, Ohio
| | - Timothy E Albertson
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, School of Medicine, University of California-Davis, Northern California Health System, Mather, California
| | - James Tumlin
- Renal Division, Department of Medicine, Emory University Medical Center, Emory University, Atlanta, Georgia
| | | | | | - George F Tidmarsh
- La Jolla Pharmaceutical Company, San Diego, California.,Stanford University, Palo Alto, California
| | - Lakhmir S Chawla
- La Jolla Pharmaceutical Company, San Diego, California.,Department of Medicine, Veterans Affairs Medical Center, San Diego, California; and
| | - Marlies Ostermann
- Department of Critical Care, Guy's & St. Thomas' Hospital, King's College London, London, United Kingdom
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23
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Cohen J, Bellomo R, Billot L, Burrell LM, Evans DM, Finfer S, Hammond NE, Li Q, Liu D, McArthur C, McWhinney B, Moore J, Myburgh J, Peake S, Pretorius C, Rajbhandari D, Rhodes A, Saxena M, Ungerer JPJ, Young MJ, Venkatesh B. Plasma Cortisol, Aldosterone, and Ascorbic Acid Concentrations in Patients with Septic Shock Do Not Predict Treatment Effect of Hydrocortisone on Mortality. A Nested Cohort Study. Am J Respir Crit Care Med 2020; 202:700-707. [PMID: 32396775 DOI: 10.1164/rccm.202002-0281oc] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations.Methods: From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand.Measurements and Main Results: There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13; P = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32; P = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04; P = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22; P = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27; P = 0.04), but total cortisol, aldosterone, and ascorbic acid were not.Conclusions: In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome.
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Affiliation(s)
- Jeremy Cohen
- The George Institute for Global Health, Sydney, New South Wales, Australia.,Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.,Royal Brisbane Clinical Unit.,The Wesley Hospital, Brisbane, Queensland, Australia
| | | | - Laurent Billot
- The George Institute for Global Health, Sydney, New South Wales, Australia.,Faculty of Medicine and
| | - Louise M Burrell
- Austin Health, Melbourne, Victoria, Australia.,Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - David M Evans
- Diamantina Institute, and.,Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
| | - Simon Finfer
- The George Institute for Global Health, Sydney, New South Wales, Australia.,Faculty of Medicine and.,Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia.,Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Naomi E Hammond
- The George Institute for Global Health, Sydney, New South Wales, Australia.,Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia.,Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Qiang Li
- The George Institute for Global Health, Sydney, New South Wales, Australia
| | - David Liu
- Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Colin McArthur
- Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand
| | | | - John Moore
- Sunshine Coast University Hospital, Sunshine Coast, Queensland, Australia
| | - John Myburgh
- The George Institute for Global Health, Sydney, New South Wales, Australia.,Faculty of Medicine and.,St. George Hospital, University of New South Wales, Sydney, New South Wales, Australia
| | - Sandra Peake
- The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.,University of Adelaide, Adelaide, South Australia, Australia.,Monash University, Melbourne, Victoria, Australia
| | | | | | | | - Manoj Saxena
- The George Institute for Global Health, Sydney, New South Wales, Australia
| | | | - Morag J Young
- Hudson Institute of Medical Research, Clayton, Victoria, Australia
| | - Balasubramanian Venkatesh
- The George Institute for Global Health, Sydney, New South Wales, Australia.,The Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia.,The Wesley Hospital, Brisbane, Queensland, Australia.,Faculty of Medicine and
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24
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Abstract
The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone and the effectiveness of angiotensin II in treating vasodilatory shock have renewed interest in the role of the mineralocorticoid axis in critical illness. Glucocorticoids have variable interactions at the mineralocorticoid receptor. Similarly, mineralocorticoid receptor-aldosterone interactions differ from mineralocorticoid receptor-glucocorticoid interactions and predicate receptor-ligand interactions that differ with respect to cellular effects. Hyperreninemic hypoaldosteronism or selective hypoaldosteronism, an impaired adrenal response to increasing renin levels, occurs in a subgroup of hemodynamically unstable critically ill patients. The suggestion is that there is a defect at the level of the adrenal zona glomerulosa associated with a high mortality rate that may represent an adaptive response aimed at increasing cortisol levels. Furthermore, cross-talk exists between angiotensin II and aldosterone, which needs to be considered when employing therapeutic strategies.
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25
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Leisman DE, Fernandes TD, Bijol V, Abraham MN, Lehman JR, Taylor MD, Capone C, Yaipan O, Bellomo R, Deutschman CS. Impaired angiotensin II type 1 receptor signaling contributes to sepsis-induced acute kidney injury. Kidney Int 2020; 99:148-160. [PMID: 32882263 DOI: 10.1016/j.kint.2020.07.047] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 07/16/2020] [Accepted: 07/24/2020] [Indexed: 12/26/2022]
Abstract
In sepsis-induced acute kidney injury, kidney blood flow may increase despite decreased glomerular filtration. Normally, angiotensin-II reduces kidney blood flow to maintain filtration. We hypothesized that sepsis reduces angiotensin type-1 receptor (AT1R) expression to account for this observation and tested this hypothesis in a patient case-control study and studies in mice. Seventy-three mice underwent cecal ligation and puncture (a sepsis model) or sham operation. Additionally, 94 septic mice received losartan (selective AT1R antagonist), angiotensin II without or with losartan, or vehicle. Cumulative urine output, kidney blood flow, blood urea nitrogen, and creatinine were measured. AT1R expression was assessed using ELISA, qPCR, and immunofluorescence. A blinded pathologist evaluated tissue for ischemic injury. AT1R expression was compared in autopsy tissue from seven patients with sepsis to that of the non-involved portion of kidney from ten individuals with kidney cancer and three non-infected but critically ill patients. By six hours post ligation/puncture, kidney blood flow doubled, blood urea nitrogen rose, and urine output fell. Concurrently, AT1R expression significantly fell 2-fold in arterioles and the macula densa. Creatinine significantly rose by 24 hours and sham operation did not alter measurements. Losartan significantly exacerbated ligation/puncture-induced changes in kidney blood flow, blood urea nitrogen, creatinine, and urine output. There was no histologic evidence of cortical ischemia. Significantly, angiotensin II prevented changes in kidney blood flow, creatinine, and urine output compared to vehicle. Co-administering losartan with angiotensin-II reversed this protection. Relative to both controls, patients with sepsis had low AT1R expression in arterioles and macula densa. Thus, murine cecal ligation/puncture and clinical sepsis decrease renal AT1R expression. Angiotensin II prevents functional changes while AT1R-blockade exacerbates them independent of ischemia in mice.
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Affiliation(s)
- Daniel E Leisman
- Icahn School of Medicine at Mount Sinai, New York, New York, USA; Sepsis Research Laboratory, Feinstein Institute for Medical Research, Manhasset, New York, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
| | - Tiago D Fernandes
- Sepsis Research Laboratory, Feinstein Institute for Medical Research, Manhasset, New York, USA; Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, New York, USA
| | - Vanesa Bijol
- Department of Pathology, North Shore University Hospital, Manhasset, New York, USA; Zucker School of Medicine at Hofstra-Northwell, Hempstead, New York, USA
| | - Mabel N Abraham
- Sepsis Research Laboratory, Feinstein Institute for Medical Research, Manhasset, New York, USA; Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, New York, USA
| | - Jake R Lehman
- Sepsis Research Laboratory, Feinstein Institute for Medical Research, Manhasset, New York, USA; Zucker School of Medicine at Hofstra-Northwell, Hempstead, New York, USA
| | - Matthew D Taylor
- Sepsis Research Laboratory, Feinstein Institute for Medical Research, Manhasset, New York, USA; Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, New York, USA; Zucker School of Medicine at Hofstra-Northwell, Hempstead, New York, USA
| | - Christine Capone
- Sepsis Research Laboratory, Feinstein Institute for Medical Research, Manhasset, New York, USA; Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, New York, USA; Zucker School of Medicine at Hofstra-Northwell, Hempstead, New York, USA
| | - Omar Yaipan
- Sepsis Research Laboratory, Feinstein Institute for Medical Research, Manhasset, New York, USA; Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, New York, USA
| | - Rinaldo Bellomo
- Data Analytics, Research and Evaluation (DARE) Centre, Austin Hospital, University of Melbourne, Melbourne, Australia; Department of Intensive Care, Austin Hospital, Melbourne, Australia; Centre of Integrated Critical Care, University of Melbourne, Melbourne, Australia; School of Medicine, University of Melbourne, Melbourne, Australia
| | - Clifford S Deutschman
- Sepsis Research Laboratory, Feinstein Institute for Medical Research, Manhasset, New York, USA; Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, New York, USA; Zucker School of Medicine at Hofstra-Northwell, Hempstead, New York, USA
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26
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Ugan RA, Un H, Gurbuz MA, Kaya G, Kahramanlar A, Aksakalli-Magden ZB, Halici Z, Cadirci E. Possible contribution of the neprilysin/ACE pathway to sepsis in mice. Life Sci 2020; 258:118177. [PMID: 32738364 DOI: 10.1016/j.lfs.2020.118177] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/19/2020] [Accepted: 07/27/2020] [Indexed: 12/16/2022]
Abstract
AIM Omapatrilat is an antagonist of angiotensin-converting (ACE) and neprilysin-neuropeptidase (NEP) enzymes. The aim of our study is to show that omapatrilat may have beneficial effects as a treatment for polymicrobial sepsis. MAIN METHODS A cecal ligation and puncture (CLP) sepsis model was used to evaluate 10 and 20 mg/kg doses of omapatrilat in mice (n = 30) fasted for 12 h. The lungs were removed 12 h after CLP, and lung levels of cytokines (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], NF-κB), iNOS and eNOS mRNA expression, GSH and MDA levels, and ACE and NEP activities were determined. Histopathological examinations were also performed. KEY FINDINGS Omapatrilat treatment provided a dose-dependent reduction in oxidative stress and inflammatory parameters in lung tissues. Omapatrilat administration decreased lung iNOS and eNOS mRNA levels at 20 mg/kg dose. Histopathological analysis revealed a decline in the thickening and edema areas in the alveolar septa in the Sepsis+OMA20 group. SIGNIFICANCE Omapatrilat, a dual ACE and NEP inhibitor, protected lung tissue from sepsis damage by reducing ACE and NEP activities, by decreasing the mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and NF-κB), by suppressing leukocyte infiltration and edema, by restoring iNOS and eNOS levels, and by restoring SOD activity and GSH and MDA levels, thereby reducing oxidative stress.
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Affiliation(s)
- Rustem Anil Ugan
- Ataturk University Faculty of Pharmacy, Department of Pharmacology, Erzurum, Turkey.
| | - Harun Un
- Agri Ibrahim Cecen University Faculty of Pharmacy, Department of Biochemistry, Agri, Turkey
| | - Muhammed Ali Gurbuz
- Ataturk University Faculty of Medicine, Department of Histology and Embryology, Erzurum, Turkey
| | - Gokce Kaya
- Ataturk University Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey
| | - Aysenur Kahramanlar
- Ataturk University Faculty of Pharmacy, Department of Biochemistry, Erzurum, Turkey
| | | | - Zekai Halici
- Ataturk University Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey; Ataturk University Clinical Research, Development and Design Application and Research Center, Erzurum, Turkey
| | - Elif Cadirci
- Ataturk University Faculty of Medicine, Department of Pharmacology, Erzurum, Turkey; Ataturk University Clinical Research, Development and Design Application and Research Center, Erzurum, Turkey
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27
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Plasma Renin Concentration is Associated With Hemodynamic Deficiency and Adverse Renal Outcome in Septic Shock. Shock 2020; 52:e22-e30. [PMID: 30407370 DOI: 10.1097/shk.0000000000001285] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND In septic shock, both systemic vasodilatation and glomerular arteriole dilatation are responsible for the drop in glomerular filtration observed in early acute kidney injury. Angiotensin II has been shown to act on both mechanisms. Our objective was to evaluate the impact of renin angiotensin system activation, on hemodynamic deficiency and renal outcome in patient with septic shock and to assess whether urinary sodium could be a reliable test for high plasma renin concentration screening. METHODS This was a prospective and observational study. Inclusion criteria were early septic shock (first episode), dose of norepinephrine ≥ 0.25 μg/kg/min, before the start of substitutive corticosteroids. Plasma renin concentration, plasma aldosterone concentration, and urinary sodium were measured at inclusion. Renal outcome, organ deficiency, and 28-day survival were followed. RESULTS Plasma renin concentration was associated with worse hemodynamic deficiency and adverse renal outcome. Natriuresis was associated with shock severity but was not associated with renal outcome. Low natriuresis (< 20 mM) was associated with higher renin concentration. Those two variables were only weakly correlated. CONCLUSION Plasma renin concentration is associated with adverse renal outcome, probably through shock severity and insufficient glomerular efferent arterioles vasoconstriction. An association was observed between low natriuresis and high plasma renin concentration.
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28
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Meresse Z, Medam S, Mathieu C, Duclos G, Vincent JL, Leone M. Vasopressors to treat refractory septic shock. Minerva Anestesiol 2020; 86. [DOI: 10.23736/s0375-9393.20.13826-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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29
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Yamamoto R, Nahara I, Toyosaki M, Fukuda T, Masuda Y, Fujishima S. Hydrocortisone with fludrocortisone for septic shock: a systematic review and meta-analysis. Acute Med Surg 2020; 7:e563. [PMID: 32995018 PMCID: PMC7507448 DOI: 10.1002/ams2.563] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 07/25/2020] [Accepted: 08/02/2020] [Indexed: 12/24/2022] Open
Abstract
AIM Combined hydrocortisone and fludrocortisone therapy for septic shock has not been evaluated with an independent systematic review. We aimed to elucidate the beneficial effects of a dual corticosteroid treatment regime involving both hydrocortisone and fludrocortisone for adult patients with septic shock on mortality. METHODS We searched the Medline, Cochrane CENTRAL, and ICHUSHI databases for reports published before April 2019. We included randomized controlled trials that compared the use of both hydrocortisone and fludrocortisone with either corticosteroid-free or hydrocortisone-only treatments on adult patients with septic shock. Three researchers independently reviewed the studies. The meta-analyses were undertaken to assess primary outcome (28-day mortality) and secondary outcomes (in-hospital mortality, long-term mortality, shock reversal, and adverse events). RESULTS Among the four studies eligible for data synthesis, we included 2,050 patients from three studies for quantitative synthesis. All studies used similar regimens (hydrocortisone and fludrocortisone for 7 days without tapering). The 28-day mortality rate was reduced after dual corticosteroid treatment (risk ratio, 0.88; 95% confidence intervals [CI], 0.78-0.99). The heterogeneity between the studies was low (I 2 = 0%). Patients who underwent dual corticosteroid treatment had lower long-term mortality rates (risk ratio, 0.90; 95% CI, 0.83-0.98) and higher rate of shock reversal after 28 days (odds ratio, 1.06; 95% CI, 1.01-1.12) than control patients. Adverse events (except for hyperglycemia) were similar among the treatment groups. CONCLUSIONS The available evidence suggests that a combination of fludrocortisone and hydrocortisone is more effective than adjunctive therapy and could be recommended for septic shock.
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Affiliation(s)
- Ryo Yamamoto
- Department of Emergency and Critical Care MedicineKeio University School of MedicineTokyoJapan
| | - Isao Nahara
- Department of Anesthesiology and Critical Care MedicineNagoya Daini Red Cross HospitalNagoyaJapan
| | - Mitsunobu Toyosaki
- Department of Emergency and Critical Care MedicineKeio University School of MedicineTokyoJapan
| | - Tatsuma Fukuda
- Department of Emergency and Critical Care MedicineGraduate School of MedicineUniversity of the RyukyusOkinawaJapan
| | - Yoshiki Masuda
- Department of Intensive Care MedicineSapporo Medical University School of MedicineSapporoJapan
| | - Seitaro Fujishima
- Center for General Medicine EducationKeio University School of MedicineTokyoJapan
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30
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Steroids Redux: Targeting the Mineralocorticoid Axis in Sepsis. Crit Care Med 2019; 45:1582-1583. [PMID: 28816849 DOI: 10.1097/ccm.0000000000002511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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31
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Jadhav AP, Sadaka FG. Angiotensin II in septic shock. Am J Emerg Med 2019; 37:1169-1174. [PMID: 30935784 DOI: 10.1016/j.ajem.2019.03.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 03/13/2019] [Accepted: 03/18/2019] [Indexed: 01/21/2023] Open
Abstract
Septic shock is a life threatening condition and a medical emergency. It is associated with organ dysfunction and hypotension despite optimal volume resuscitation. Refractory septic shock carries a very high rate of mortality and is associated with ischemic and arrhythmogenic complications from high dose vasopressors. Angiotensin II (AT-II) is a product of the renin-angiotensin-aldosterone system. It is a vasopressor agent that has been recently approved by FDA to be used in conjunction with other vasopressors (catecholamines) in refractory shock and to reduce catecholamine requirements. We have reviewed the physiology and current literature on AT-II in refractory septic/vasodilatory shock. Larger trials with longer duration of follow-up are warranted to address the questions which are unanswered by the ATHOS-3 trial, especially pertaining to its effects on lungs, brain, microcirculation, inflammation, and venous thromboembolism risk.
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Affiliation(s)
- Amar P Jadhav
- Intensivist, SSM St. Mary's Hospital, Richmond Heights, St. Louis, United States of America..
| | - Farid G Sadaka
- Clinical Associate Professor, Critical care/Neurocritical care, Mercy Hospital St.Louis, St. Louis University School of Medicine Program, United States of America
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32
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Heming N, Sivanandamoorthy S, Meng P, Bounab R, Annane D. Immune Effects of Corticosteroids in Sepsis. Front Immunol 2018; 9:1736. [PMID: 30105022 PMCID: PMC6077259 DOI: 10.3389/fimmu.2018.01736] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Accepted: 07/13/2018] [Indexed: 12/29/2022] Open
Abstract
Sepsis, a life-threatening organ dysfunction, results from a dysregulated host response to invading pathogens that may be characterized by overwhelming systemic inflammation or some sort of immune paralysis. Sepsis remains a major cause of morbidity and mortality. Treatment is nonspecific and relies on source control and organ support. Septic shock, the most severe form of sepsis is associated with the highest rate of mortality. Two large multicentre trials, undertaken 15 years apart, found that the combination of hydrocortisone and fludrocortisone significantly reduces mortality in septic shock. The corticosteroids family is composed of several molecules that are usually characterized according to their glucocorticoid and mineralocorticoid power, relative to hydrocortisone. While the immune effects of glucocorticoids whether mediated or not by the intracellular glucocorticoid receptor have been investigated for several decades, it is only very recently that potential immune effects of mineralocorticoids via non-renal mineralocorticoid receptors have gained popularity. We reviewed the respective role of glucocorticoids and mineralocorticoids in counteracting sepsis-associated dysregulated immune systems.
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Affiliation(s)
- Nicholas Heming
- General Intensive Care Unit, Raymond Poincaré Hospital, Garches, France.,U1173 Laboratory Inflammation and Infection, University of Versailles SQY-Paris Saclay - INSERM, Montigny-Le-Bretonneux, France
| | | | - Paris Meng
- General Intensive Care Unit, Raymond Poincaré Hospital, Garches, France
| | - Rania Bounab
- General Intensive Care Unit, Raymond Poincaré Hospital, Garches, France
| | - Djillali Annane
- General Intensive Care Unit, Raymond Poincaré Hospital, Garches, France.,U1173 Laboratory Inflammation and Infection, University of Versailles SQY-Paris Saclay - INSERM, Montigny-Le-Bretonneux, France
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Abstract
Angiotensin II (Ang II), part of the renin-angiotensin-aldosterone system (RAS), is a potent vasoconstrictor and has been recently approved for use by the US Food and Drug Administration in high-output shock. Though not a new drug, the recently published Angiotensin II for the Treatment of High Output Shock (ATHOS-3) trial, as well as a number of retrospective analyses have sparked renewed interest in the use of Ang II, which may have a role in treating refractory shock. We describe refractory shock, the unique mechanism of action of Ang II, RAS dysregulation in shock, and the evidence supporting the use of Ang II to restore blood pressure. Evidence suggests that Ang II may preferentially be of benefit in acute kidney injury and acute respiratory distress syndrome, where the RAS is known to be disrupted. Additionally, there may be a role for Ang II in cardiogenic shock, angiotensin converting enzyme inhibitor overdose, cardiac arrest, liver failure, and in settings of extracorporeal circulation.
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Affiliation(s)
- Rachel L Bussard
- Critical Care Pharmacy Specialist, Department of Pharmacy, Emory St Joseph's Hospital, Atlanta, GA, USA
| | - Laurence W Busse
- Department of Critical Care, Emory St Joseph's Hospital, Atlanta, GA, USA,
- Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, USA,
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Chung KS, Song JH, Jung WJ, Kim YS, Kim SK, Chang J, Park MS. Implications of Plasma Renin Activity and Plasma Aldosterone Concentration in Critically Ill Patients with Septic Shock. Korean J Crit Care Med 2017; 32:142-153. [PMID: 31723628 PMCID: PMC6786707 DOI: 10.4266/kjccm.2017.00094] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 04/15/2017] [Accepted: 04/15/2017] [Indexed: 01/18/2023] Open
Abstract
Background The renin-angiotensin-aldosterone system is closely associated with volume status and vascular tone in septic shock. The present study aimed to assess whether plasma renin activity (PRA) and plasma aldosterone concentration (PAC) measurements compared with conventional severity indicators are associated with mortality in patients with septic shock. Methods We evaluated 105 patients who were admitted for septic shock. Plasma levels of the biomarkers PRA and PAC, the PAC/PRA ratio, C-reactive protein (CRP) level, and cortisol level on days 1, 3, and 7 were serially measured. During the intensive care unit stay, relevant clinical information and laboratory results were recorded. Results Patients were divided into two groups according to 28-day mortality: survivors (n = 59) and non-survivors (n = 46). The survivor group showed lower PRA, PAC, Acute Physiologic and Chronic Health Evaluation (APACHE) II score, and Sequential Organ Failure Assessment (SOFA) score than did the non-survivor group (all P < 0.05). The SOFA score was positively correlated with PRA (r = 0.373, P < 0.001) and PAC (r = 0.316, P = 0.001). According to receiver operating characteristic analysis, the areas under the curve of PRA and PAC to predict 28-day mortality were 0.69 (95% confidence interval [CI], 0.58 to 0.79; P = 0.001) and 0.67 (95% CI, 0.56 to 0.77; P = 0.003), respectively, similar to the APACHE II scores and SOFA scores. In particular, the group with PRA value ≥3.5 ng ml-1 h-1 on day 1 showed significantly greater mortality than did the group with PRA value <3.5 ng ml-1 h-1 (log-rank test, P < 0.001). According to multivariate analysis, SOFA score (hazard ratio, 1.11; 95% CI, 1.01 to 1.22), PRA value ≥3.5 ng ml-1 h-1 (hazard ratio, 3.25; 95% CI, 1.60 to 6.60), previous history of cancer (hazard ratio, 3.44; 95% CI, 1.72 to 6.90), and coronary arterial occlusive disease (hazard ratio, 2.99; 95% CI, 1.26 to 7.08) were predictors of 28-day mortality. Conclusions Elevated PRA is a useful biomarker to stratify the risk of critically ill patients with septic shock and is a prognostic predictor of 28-day mortality.
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Affiliation(s)
- Kyung Soo Chung
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Joo Han Song
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Won Jai Jung
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Young Sam Kim
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Se Kyu Kim
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Joon Chang
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Moo Suk Park
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Sugar or salt? The relative roles of the glucocorticoid and mineralocorticoid axes in traumatic shock. J Trauma Acute Care Surg 2016; 79:1023-9. [PMID: 26680140 DOI: 10.1097/ta.0000000000000800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Glucocorticoid deficiency (GD) has been proposed as a key contributor to shock states, but the presence and role of acute mineralocorticoid deficiency may be of equal or greater significance. We sought to analyze the incidence and degree of acute mineralocorticoid deficiency and GD in an animal model of severe hemorrhage and shock. METHODS Fifty-seven swine underwent 35% volume-controlled hemorrhage followed by aortic cross-clamping for 50 minutes to induce truncal ischemia-reperfusion. Protocol-guided resuscitation was performed. Laboratory analysis included cortisol, aldosterone, and plasma renin activity. The aldosterone-to-renin ratio (ARR) was calculated at each time point, and changes were correlated to markers of perfusion. RESULTS Mean baseline cortisol levels were 5.8 μg/dL. Following hemorrhage, there was a significant increase in mean cortisol to 9.2 μg/dL (p < 0.001). After 1 hour of reperfusion, there was no change in mean cortisol levels (9.8 μg/dL, p = 0.12). Mean baseline aldosterone was 13.3 pg/mL. Aldosterone levels before cross-clamp removal increased significantly to 115.1 pg/mL (p < 0.001) and then rapidly declined to 49.2 pg/mL (p < 0.001) after 1 hour of reperfusion. Conversely, baseline plasma renin activity was 0.75 ng/mL per hour and increased significantly before cross-clamp removal (1.8) and at 1 hour (8.9, both p < 0.001). The ARR at baseline was 96.1 and increased to 113.5 (p = 0.68) before cross-clamp removal but significantly declined following 1 hour of reperfusion to 7.6 (p < 0.001). Overall, this represented a 93% reduction in mean ARR following reperfusion. The degree of aldosterone deficiency correlated with degree of systemic shock as measured by arterial base deficit (r = 0.47, p = 0.04), while cortisol showed no correlation. CONCLUSION Hemorrhagic shock with ischemia-reperfusion injury resulted in only modest impact on the glucocorticoid axis, but major dysfunction of the mineralocorticoid axis and severe hyperreninemic hypoaldosteronism. The degree of aldosterone deficiency may provide prognostic information or offer potential targets for pharmacologic intervention. LEVEL OF EVIDENCE Diagnostic study, level III.
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Semler MW, Marney AM, Rice TW, Nian H, Yu C, Wheeler AP, Brown NJ. B-Type Natriuretic Peptide, Aldosterone, and Fluid Management in ARDS. Chest 2016; 150:102-11. [PMID: 27018313 DOI: 10.1016/j.chest.2016.03.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 03/02/2016] [Accepted: 03/07/2016] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Conservative fluid management increases ventilator-free days without influencing overall mortality in acute respiratory distress syndrome. Plasma concentrations of B-type natriuretic peptide (a marker of ventricular filling) or aldosterone (a marker of effective circulating volume) may identify patients for whom fluid management impacts survival. METHODS This was a retrospective analysis of the Fluid and Catheter Treatment Trial (FACTT), a randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. Using plasma collected at study enrollment, we measured B-type natriuretic peptide and aldosterone by immunoassay. Multivariable analyses examined the interaction between B-type natriuretic peptide or aldosterone concentration and fluid strategy with regard to 60-day in-hospital mortality. RESULTS Among 625 patients with adequate plasma, median B-type natriuretic peptide concentration was 825 pg/mL (interquartile range, 144-1,574 pg/mL), and median aldosterone was 2.49 ng/dL (interquartile range, 1.1-4.3 ng/dL). B-type natriuretic peptide did not predict overall mortality, correlate with fluid balance, or modify the effect of conservative vs liberal fluid management on outcomes. In contrast, among patients with lower aldosterone concentrations, conservative fluid management increased ventilator-free days (17.1 ± 9.8 vs 12.5 ± 10.3, P < .001) and decreased mortality (19% vs 30%, P = .03) (P value for interaction = .01). CONCLUSIONS In acute respiratory distress syndrome, B-type natriuretic peptide does not modify the effect of fluid management on outcomes. Lower initial aldosterone appears to identify patients for whom conservative fluid management may improve mortality.
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Affiliation(s)
- Matthew W Semler
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN.
| | | | - Todd W Rice
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Hui Nian
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Chang Yu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Arthur P Wheeler
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Nancy J Brown
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
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Corrêa TD, Takala J, Jakob SM. Angiotensin II in septic shock. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2015; 19:98. [PMID: 25886853 PMCID: PMC4360936 DOI: 10.1186/s13054-015-0802-3] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2015 and co-published as a series in Critical Care. Other articles in the series can be found online at http://ccforum.com/series/annualupdate2015. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.
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Affiliation(s)
- Thiago D Corrêa
- Hospital Israelita Albert Einstein, Intensive Care Unit, São Paulo, Brazil.
| | - Jukka Takala
- Department of Intensive Care Medicine, Bern University Hospital, Inselspital, Bern, Switzerland. .,University of Bern, Bern, Switzerland.
| | - Stephan M Jakob
- Department of Intensive Care Medicine, Bern University Hospital, Inselspital, Bern, Switzerland. .,University of Bern, Bern, Switzerland.
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Gójska-Zygner O, Zygner W. Hyperaldosteronism and its association with hypotension and azotaemia in canine babesiosis. Vet Q 2014; 35:37-42. [PMID: 25347616 DOI: 10.1080/01652176.2014.981765] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
BACKGROUND The previous work on canine babesiosis revealed hypokalaemia and increased fractional excretion of potassium in infected dogs suggesting a role for aldosterone in the loss of potassium via the kidneys in affected dogs. Moreover, hypotension, which is one of the complications of canine babesiosis leading to renal failure, may induce secondary hyperaldosteronism. ANIMALS AND METHODS In this study, the serum aldosterone concentration was determined in 14 dogs infected with Babesia canis. The Mann-Whitney U test was used to compare serum aldosterone concentration and blood pressure between these dogs and 10 healthy dogs. Spearman's rank correlations between serum aldosterone concentration and blood pressure and between serum aldosterone and urea and creatinine concentrations were calculated. RESULTS Increased concentrations of aldosterone above reference intervals were observed in only 4 out of the 14 dogs. The results showed significantly (p < 0.05) higher serum aldosterone concentrations and lower blood pressures in infected dogs in comparison to healthy dogs, and significantly negative correlations between aldosterone concentration and systolic arterial pressure (r = -0.63), diastolic arterial pressure (r = -0.67) and mean arterial pressure (r = -0.65). Serum aldosterone concentration was also significantly correlated with serum urea concentration (r = 0.72), serum creatinine concentration (r = 0.69) and serum potassium concentration (r = -0.57). CONCLUSION The results of this study show hyperaldosteronism in some cases of canine babesiosis as a possible response to hypotension. However, both the hypotension and severe azotaemia observed in dogs infected with B. canis and associated hyperaldosteronaemia suggest that this response is insufficient.
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Moraes RB, Friedman G, Viana MV, Tonietto T, Saltz H, Czepielewski MA. Aldosterone secretion in patients with septic shock: a prospective study. ACTA ACUST UNITED AC 2014; 57:636-41. [PMID: 24343633 DOI: 10.1590/s0004-27302013000800009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Accepted: 05/02/2013] [Indexed: 12/26/2022]
Abstract
OBJECTIVE To assess serum levels of the main factors that regulate the activation of the zona glomerulosa and aldosterone production in patients with septic shock, as well as their response to a high-dose (250 µg) adrenocorticotropic hormone (ACTH) stimulation test. SUBJECTS AND METHODS In 27 patients with septic shock, baseline levels of aldosterone, cortisol, ACTH, renin, sodium, potassium, and lactate were measured, followed by a cortrosyn test. RESULTS Renin correlated with baseline aldosterone and its variation after cortrosyn stimulation. Baseline cortisol and its variation did not correlate with ACTH. Only three patients had concomitant dysfunction of aldosterone and cortisol secretion. CONCLUSIONS Activation of the zona glomerulosa and zona fasciculata are independent. Aldosterone secretion is dependent on the integrity of the renin-angiotensin-aldosterone system, whereas cortisol secretion does not appear to depend predominantly on the hypothalamic-pituitary-adrenal axis. These results suggest that activation of the adrenal gland in critically ill patients occurs by multiple mechanisms.
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Laviolle B, Donal E, Le Maguet P, Lainé F, Bellissant E. Low doses of fludrocortisone and hydrocortisone, alone or in combination, on vascular responsiveness to phenylephrine in healthy volunteers. Br J Clin Pharmacol 2013; 75:423-30. [PMID: 22703532 DOI: 10.1111/j.1365-2125.2012.04359.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 06/01/2012] [Indexed: 12/15/2022] Open
Abstract
AIMS A single administration of hydrocortisone has been shown to enhance the pressor response to phenylephrine in healthy volunteers and to norepinephrine in septic shock patients. Similar data do not exist for fludrocortisone. Since there continues to be disagreement about the utility of fludrocortisone in septic shock, we assessed the effects of a single administration of low doses of hydrocortisone (50 mg intravenously) and fludrocortisone (50 μg orally), given either alone or in combination, on phenylephrine mean arterial pressure and cardiac systolic and diastolic function dose-response relationships in 12 healthy male volunteers with hypo-aldosteronism induced by intravenous sodium loading. METHODS This was a placebo-controlled, randomized, double-blind, crossover study performed according to a 2 × 2 factorial design. Subjects received first a 2000 ml infusion of NaCl 0.9% during 2 h. Then fludrocortisone 50 μg (or its placebo) was administered orally and hydrocortisone 50 mg (or its placebo) was injected intravenously. At 1.5 h after treatment administration, incremental doses of phenylephrine were infused (from 0.01 to 3 μg kg(-1) min(-1)), each dose being infused during 5 min. RESULTS Both fludrocortisone (P < 0.001) and hydrocortisone (P = 0.002) induced a significant decrease in pressor response to phenylephrine, their effects being additive (fludrocortisone × hydrocortisone interaction, P = 0.792). The two drugs did not induce any detectable cardiac effect. CONCLUSIONS Single administrations of fludrocortisone and hydrocortisone decreased the pressor response to phenylephrine in healthy volunteers with hypo-aldosteronism. These similar effects of hydrocortisone and fludrocortisone probably express a rapid non-genomic vasodilating effect of the two steroids in the context of acute volume loading.
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Affiliation(s)
- Bruno Laviolle
- Inserm, CIC-P 0203 Clinical Investigation Centre, Rennes, France
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Dembek KA, Onasch K, Hurcombe SDA, MacGillivray KC, Slovis NM, Barr BS, Reed SM, Toribio RE. Renin-Angiotensin-aldosterone system and hypothalamic-pituitary-adrenal axis in hospitalized newborn foals. J Vet Intern Med 2013; 27:331-8. [PMID: 23398197 DOI: 10.1111/jvim.12043] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 12/03/2012] [Accepted: 12/20/2012] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND The renin-angiotensin-aldosterone system (RAAS) and hypothalamic-pituitary-adrenal axis (HPAA) and their interactions during illness and hypoperfusion are important to maintain organ function. HPAA dysfunction and relative adrenal insufficiency (RAI) are common in septic foals. Information is lacking on the RAAS and mineralocorticoid response in the context of RAI in newborn sick foals. OBJECTIVES/HYPOTHESIS To investigate the RAAS, as well as HPAA factors that interact with the RAAS, in hospitalized foals, and to determine their association with clinical findings. We hypothesized that critical illness in newborn foals results in RAAS activation, and that inappropriately low aldosterone concentrations are part of the RAI syndrome of critically ill foals. ANIMALS A total of 167 foals ≤3 days of age: 133 hospitalized (74 septic, 59 sick nonseptic) and 34 healthy foals. METHODS Prospective, multicenter, cross-sectional study. Blood samples were collected on admission. Plasma renin activity (PRA) and angiotensin-II (ANG-II), aldosterone, ACTH, and cortisol concentrations were measured in all foals. RESULTS ANG-II, aldosterone, ACTH, and cortisol concentrations as well as ACTH/aldosterone and ACTH/cortisol ratios were higher in septic foals compared with healthy foals (P < .05). No difference in PRA between groups was found. High serum potassium and low serum chloride concentrations were associated with hyperaldosteronemia in septic foals. CONCLUSIONS AND CLINICAL IMPORTANCE RAAS activation in critically ill foals is characterized by increased ANG-II and aldosterone concentrations. Inappropriately low cortisol and aldosterone concentrations defined as high ACTH/cortisol and ACTH/aldosterone ratios in septic foals suggest that RAI is not restricted to the zona fasciculata in critically ill newborn foals.
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Affiliation(s)
- K A Dembek
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH
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Molenaar N, Bijkerk RM, Beishuizen A, Hempen CM, de Jong MFC, Vermes I, van der Sluijs Veer G, Girbes ARJ, Groeneveld ABJ. Steroidogenesis in the adrenal dysfunction of critical illness: impact of etomidate. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2012; 16:R121. [PMID: 22781364 PMCID: PMC3580698 DOI: 10.1186/cc11415] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2012] [Accepted: 07/10/2012] [Indexed: 12/15/2022]
Abstract
Introduction This study was aimed at characterizing basal and adrenocorticotropic hormone (ACTH)-induced steroidogenesis in sepsis and nonsepsis patients with a suspicion of critical illness-related corticosteroid insufficiency (CIRCI), taking the use of etomidate-inhibiting 11β-hydroxylase into account. Method This was a prospective study in a mixed surgical/medical intensive care unit (ICU) of a university hospital. The patients were 62 critically ill patients with a clinical suspicion of CIRCI. The patients underwent a 250-μg ACTH test (n = 67). ACTH, adrenal steroids, substrates, and precursors (modified tandem mass spectrometry) also were measured. Clinical characteristics including use of etomidate to facilitate intubation (n = 14 within 72 hours of ACTH testing) were recorded. Results At the time of ACTH testing, patients had septic (n = 43) or nonseptic critical illness (n = 24). Baseline cortisol directly related to sepsis and endogenous ACTH, independent of etomidate use. Etomidate was associated with a lower baseline cortisol and cortisol/11β-deoxycortisol ratio as well as higher 11β-deoxycortisol, reflecting greater 11β-hydroxylase inhibition in nonsepsis than in sepsis. Cortisol increases < 250 mM in exogenous ACTH were associated with relatively low baseline (HDL-) cholesterol, and high endogenous ACTH with low cortisol/ACTH ratio, independent of etomidate. Although cortisol increases with exogenous ACTH, levels were lower in sepsis than in nonsepsis patients, and etomidate was associated with diminished increases in cortisol with exogenous ACTH, so that its use increased, albeit nonsignificantly, low cortisol increases to exogenous ACTH from 38% to 57%, in both conditions. Conclusions A single dose of etomidate may attenuate stimulated more than basal cortisol synthesis. However, it may only partly contribute, particularly in the stressed sepsis patient, to the adrenal dysfunction of CIRCI, in addition to substrate deficiency.
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Audibert G, Hoche J, Baumann A, Mertes PM. Désordres hydroélectrolytiques des agressions cérébrales : mécanismes et traitements. ACTA ACUST UNITED AC 2012; 31:e109-15. [DOI: 10.1016/j.annfar.2012.04.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Tolstoy NS, Aized M, McMonagle MP, Holena DN, Pascual JL, Sonnad SS, Sims CA. Mineralocorticoid deficiency in hemorrhagic shock. J Surg Res 2012; 180:232-7. [PMID: 22683082 DOI: 10.1016/j.jss.2012.05.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2012] [Revised: 04/10/2012] [Accepted: 05/04/2012] [Indexed: 12/29/2022]
Abstract
BACKGROUND In the critically ill, mineralocorticoid deficiency (MD) is associated with greater disease severity, the development of acute renal insufficiency, and increased mortality. We hypothesized that severely injured trauma patients presenting with hemorrhagic shock would demonstrate a high degree of MD. We also hypothesized that MD in these patients would be associated with increased length of stay, hypotension, fluid requirements, and acute kidney injury (AKI). MATERIALS AND METHODS Thirty-two trauma patients in hemorrhagic shock on admission to the trauma bay (SBP <90 mm Hg × 2) were enrolled. Blood samples were obtained on ICU admission and 8, 16, 24, and 48 hours later. Plasma aldosterone (PA) and renin (PR) were assayed by radioimmunoassay. MD was defined as a ratio of PA/PR ≤2. Demographic data, injury severity score, ICU and hospital length of stay, fluid requirements, mean arterial pressure, serum sodium, hypotension, and risk for AKI were compared for patients with and without MD. RESULTS At ICU admission, 48% of patients met criteria for MD. Patients with MD were significantly more likely to experience hypotension (MAP ≤60 mm Hg) during the study period. MD patients required significantly more units of blood in 48 h than non-MD patients (13 [7-22] versus 5 [2-7], P = 0.015) and had increased crystalloid requirements (18L [14-23] versus 9L [6-10], P < 0.001). MD patients were at higher risk for AKI according to RIFLE and AKIN criteria. CONCLUSIONS MD is a common entity in trauma patients presenting in hemorrhagic shock. Patients with MD required a more aggressive resuscitative effort, were more likely to experience hypotension, and had a higher risk of AKI than non-MD patients. Future studies are needed to fully understand the impact of MD following trauma and the potential role for hormonal replacement therapy.
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Hicks CW, Sweeney DA, Danner RL, Eichacker PQ, Suffredini AF, Feng J, Sun J, Behrend EN, Solomon SB, Natanson C. Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock. Crit Care Med 2012; 40:199-207. [PMID: 21926575 PMCID: PMC3242885 DOI: 10.1097/ccm.0b013e31822efa14] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
OBJECTIVE Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock but have variable effects on survival. The objective of this study was to determine whether exogenous mineralocorticoid and glucocorticoid treatments have distinct effects and whether the timing of administration alters their effects in septic shock. DESIGN, SETTING, SUBJECTS, AND INTERVENTIONS: Desoxycorticosterone, a selective mineralocorticoid agonist; dexamethasone, a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 hrs in 74 canines with staphylococcal pneumonia. MEASUREMENTS AND MAIN RESULTS Effects of desoxycorticosterone and dexamethasone were different and opposite depending on timing of administration for survival (p = .05); fluid requirements (p = .05); central venous pressures (p ≤ .007); indicators of hemoconcentration (i.e., sodium [p = .0004], albumin [p = .05], and platelet counts [p = .02]); interleukin-6 levels (p = .04); and cardiac dysfunction (p = .05). Prophylactic desoxycorticosterone treatment significantly improved survival, shock, and all the other outcomes stated, but therapeutic desoxycorticosterone did not. Conversely, prophylactic dexamethasone was much less effective for improving these outcomes compared with therapeutic dexamethasone with the exception of shock reversal. Prophylactic dexamethasone given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared with therapeutic dexamethasone (p ≤ .05), consistent with adrenal suppression. CONCLUSIONS In septic shock, mineralocorticoids are only beneficial if given prophylactically, whereas glucocorticoids are most beneficial when given close to the onset of infection. Prophylactic mineralocorticoids should be further investigated in patients at high risk to develop sepsis, whereas glucocorticoids should only be administered therapeutically to prevent adrenal suppression and worse outcomes.
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Affiliation(s)
- Caitlin W Hicks
- Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA.
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Venkatesh B, Cohen J. Adrenocortical (dys)function in septic shock - a sick euadrenal state. Best Pract Res Clin Endocrinol Metab 2011; 25:719-33. [PMID: 21925073 DOI: 10.1016/j.beem.2011.04.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
A central feature of the endocrine pathophysiology of septic shock is thought to be the existence of adrenal dysfunction. Based on changes in glucocorticoid secretion and responsiveness, protein binding, and activity. These changes have been described by the terms "Relative Adrenal Insufficiency" (RAI), or "Critical Illness Related Corticosteroid Insufficiency" (CIRCI), and form part of the rationale for trials of glucocorticoid treatment in septic shock. Diagnostic criteria for these conditions have been based on plasma cortisol profiles and have proven notoriously difficult to establish. The uncertainty in this area arises from the inability of current tests to clearly identify who is truly glucocorticoid "deficient" at a cellular level, and hence who requires supplemental glucocorticoid administration. Emerging data suggest that there may be abnormalities in the tissue activity of glucocorticoids in patients with severe sepsis and plasma profiles may not be reliable indicators of tissue glucocorticoid activity, We put forward an alternative point of view, that is the spectrum of adrenocortical dysfunction in sepsis - plasma and tissue, can be grouped under the umbrella of a "sick euadrenal syndrome" rather than an adrenocortical insufficiency.
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Affiliation(s)
- Bala Venkatesh
- Princess Alexandra and Wesley hospitals, University of Queensland, Brisbane, Australia.
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Clinical effects of adding fludrocortisone to a hydrocortisone-based shock protocol in hypotensive critically ill children. Intensive Care Med 2010; 37:518-24. [DOI: 10.1007/s00134-010-2090-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2010] [Accepted: 11/08/2010] [Indexed: 10/18/2022]
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Polito A, Lorin de la Grandmaison G, Mansart A, Louiset E, Lefebvre H, Sharshar T, Annane D. Human and experimental septic shock are characterized by depletion of lipid droplets in the adrenals. Intensive Care Med 2010; 36:1852-8. [DOI: 10.1007/s00134-010-1987-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2010] [Accepted: 04/27/2010] [Indexed: 12/21/2022]
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