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Chiari P, Fellahi JL. Myocardial protection in cardiac surgery: a comprehensive review of current therapies and future cardioprotective strategies. Front Med (Lausanne) 2024; 11:1424188. [PMID: 38962735 PMCID: PMC11220133 DOI: 10.3389/fmed.2024.1424188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 05/23/2024] [Indexed: 07/05/2024] Open
Abstract
Cardiac surgery with cardiopulmonary bypass results in global myocardial ischemia-reperfusion injury, leading to significant postoperative morbidity and mortality. Although cardioplegia is the cornerstone of intraoperative cardioprotection, a number of additional strategies have been identified. The concept of preconditioning and postconditioning, despite its limited direct clinical application, provided an essential contribution to the understanding of myocardial injury and organ protection. Therefore, physicians can use different tools to limit perioperative myocardial injury. These include the choice of anesthetic agents, remote ischemic preconditioning, tight glycemic control, optimization of respiratory parameters during the aortic unclamping phase to limit reperfusion injury, appropriate choice of monitoring to optimize hemodynamic parameters and limit perioperative use of catecholamines, and early reintroduction of cardioprotective agents in the postoperative period. Appropriate management before, during, and after cardiopulmonary bypass will help to decrease myocardial damage. This review aimed to highlight the current advancements in cardioprotection and their potential applications during cardiac surgery.
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Affiliation(s)
- Pascal Chiari
- Service d’Anesthésie Réanimation, Hôpital Universitaire Louis Pradel, Hospices Civils de Lyon, Lyon, France
- Laboratoire CarMeN, Inserm UMR 1060, Université Claude Bernard Lyon 1, Lyon, France
| | - Jean-Luc Fellahi
- Service d’Anesthésie Réanimation, Hôpital Universitaire Louis Pradel, Hospices Civils de Lyon, Lyon, France
- Laboratoire CarMeN, Inserm UMR 1060, Université Claude Bernard Lyon 1, Lyon, France
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Chang H, Chen E, Zhu T, Liu J, Chen C. Communication Regarding the Myocardial Ischemia/Reperfusion and Cognitive Impairment: A Narrative Literature Review. J Alzheimers Dis 2024; 97:1545-1570. [PMID: 38277294 PMCID: PMC10894588 DOI: 10.3233/jad-230886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2023] [Indexed: 01/28/2024]
Abstract
Coronary artery disease is a prevalent ischemic disease that results in insufficient blood supply to the heart muscle due to narrowing or occlusion of the coronary arteries. Various reperfusion strategies, including pharmacological thrombolysis and percutaneous coronary intervention, have been developed to enhance blood flow restoration. However, these interventions can lead to myocardial ischemia/reperfusion injury (MI/RI), which can cause unpredictable complications. Recent research has highlighted a compelling association between MI/RI and cognitive function, revealing pathophysiological mechanisms that may explain altered brain cognition. Manifestations in the brain following MI/RI exhibit pathological features resembling those observed in Alzheimer's disease (AD), implying a potential link between MI/RI and the development of AD. The pro-inflammatory state following MI/RI may induce neuroinflammation via systemic inflammation, while impaired cardiac function can result in cerebral under-perfusion. This review delves into the role of extracellular vesicles in transporting deleterious substances from the heart to the brain during conditions of MI/RI, potentially contributing to impaired cognition. Addressing the cognitive consequence of MI/RI, the review also emphasizes potential neuroprotective interventions and pharmacological treatments within the MI/RI model. In conclusion, the review underscores the significant impact of MI/RI on cognitive function, summarizes potential mechanisms of cardio-cerebral communication in the context of MI/RI, and offers ideas and insights for the prevention and treatment of cognitive dysfunction following MI/RI.
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Affiliation(s)
- Haiqing Chang
- Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Erya Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tao Zhu
- Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jin Liu
- Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chan Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Kashiwagi S, Mihara T, Yokoi A, Yokoyama C, Nakajima D, Goto T. Effect of remote ischemic preconditioning on lung function after surgery under general anesthesia: a systematic review and meta-analysis. Sci Rep 2023; 13:17720. [PMID: 37853024 PMCID: PMC10584824 DOI: 10.1038/s41598-023-44833-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 10/12/2023] [Indexed: 10/20/2023] Open
Abstract
Remote ischemic preconditioning (RIPC) protects organs from ischemia-reperfusion injury. Recent trials showed that RIPC improved gas exchange in patients undergoing lung or cardiac surgery. We performed a systematic search to identify randomized controlled trials involving RIPC in surgery under general anesthesia. The primary outcome was the PaO2/FIO2 (P/F) ratio at 24 h after surgery. Secondary outcomes were A-a DO2, the respiratory index, duration of postoperative mechanical ventilation (MV), incidence of acute respiratory distress syndrome (ARDS), and serum cytokine levels. The analyses included 71 trials comprising 7854 patients. Patients with RIPC showed higher P/F ratio than controls (mean difference [MD] 36.6, 95% confidence interval (CI) 12.8 to 60.4, I2 = 69%). The cause of heterogeneity was not identified by the subgroup analysis. Similarly, A-a DO2 (MD 15.2, 95% CI - 29.7 to - 0.6, I2 = 87%) and respiratory index (MD - 0.17, 95% CI - 0.34 to - 0.01, I2 = 94%) were lower in the RIPC group. Additionally, the RIPC group was weaned from MV earlier (MD - 0.9 h, 95% CI - 1.4 to - 0.4, I2 = 78%). Furthermore, the incidence of ARDS was lower in the RIPC group (relative risk 0.73, 95% CI 0.60 to 0.89, I2 = 0%). Serum TNFα was lower in the RIPC group (SMD - 0.6, 95%CI - 1.0 to - 0.3 I2 = 87%). No significant difference was observed in interleukin-6, 8 and 10. Our meta-analysis suggested that RIPC improved oxygenation after surgery under general anesthesia.Clinical trial number: This study protocol was registered in the University Hospital Medical Information Network (registration number: UMIN000030918), https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000035305.
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Affiliation(s)
- Shizuka Kashiwagi
- Department of Anesthesiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
- Department of Anesthesiology, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-Ku, Yokohama City, Kanagawa-Ken, 236-0004, Japan.
| | - Takahiro Mihara
- Department of Health Data Science, Yokohama City University Graduate School of Data Science, Yokohama, Japan
| | - Ayako Yokoi
- Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Chisaki Yokoyama
- Department of Anesthesia, Chiba Children's Hospital, Chiba, Japan
| | - Daisuke Nakajima
- Department of Anesthesiology, Yokohama City University Medical Center, Yokohama City, Japan
| | - Takahisa Goto
- Department of Anesthesiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Lucius J, Jensen JO, Tasar RR, Schleusser S, Stang FH, Mailänder P, Kisch T. Acute Microcirculatory Effects of Remote Ischemic Conditioning in Superficial Partial Thickness Burn Wounds. J Burn Care Res 2023; 44:912-917. [PMID: 36326797 DOI: 10.1093/jbcr/irac166] [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: 07/20/2023]
Abstract
Microcirculation is a critical factor in burn wound healing. Remote ischemic conditioning (RIC) has been shown to improve microcirculation in healthy skin and demonstrated ischemic protective effects on heart, kidney, and liver cells. Therefore, we examined microcirculatory effects of RIC in partial thickness burn wounds. The hypothesis of this study is that RIC improves cutaneous microcirculation in partial thickness burn wounds. Twenty patients with partial thickness burn wounds within 48 hours after trauma were included in this study. RIC was performed with an upper arm blood pressure cuff on a healthy upper arm using three ischemia cycles (5 min inflation to 200 mm Hg) followed by 10-minute reperfusion phases. The third and final reperfusion phase lasted 20 minutes. Microcirculation of the remote (lower/upper extremities or torso) burn wound was continuously quantified, using a combined Laser Doppler and white light spectrometry. The capillary blood flow in the burn wounds increased by a maximum of 9.6% after RIC (percentage change from baseline; P < .01). Relative hemoglobin was increased by a maximum of 2.8% (vs. baseline; P < .01), while cutaneous tissue oxygen saturation remained constant (P > .05). RIC improves microcirculation in partial thickness burn wounds by improving blood flow and elevating relative hemoglobin.
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Affiliation(s)
- Julia Lucius
- Department of Plastic Surgery, Hand Surgery and Burn Care Unit, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
| | - Jan-Oluf Jensen
- Department of Plastic Surgery, Hand Surgery and Burn Care Unit, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
| | - Raphael R Tasar
- Department of Plastic Surgery, Hand Surgery and Burn Care Unit, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
| | - Sophie Schleusser
- Department of Plastic Surgery, Hand Surgery and Burn Care Unit, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
| | - Felix H Stang
- Department of Plastic Surgery, Hand Surgery and Burn Care Unit, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
| | - Peter Mailänder
- Department of Plastic Surgery, Hand Surgery and Burn Care Unit, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
| | - Tobias Kisch
- Department of Plastic Surgery, Hand Surgery and Burn Care Unit, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
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Ganji N, Biouss G, Sabbatini S, Li B, Lee C, Pierro A. Remote ischemic conditioning in necrotizing enterocolitis. Semin Pediatr Surg 2023; 32:151312. [PMID: 37295298 DOI: 10.1016/j.sempedsurg.2023.151312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Necrotizing enterocolitis (NEC) is a devastating intestinal inflammatory disorder, most prevalent in premature infants, and associated with a high mortality rate that has remained unchanged in the past two decades. NEC is characterized by inflammation, ischemia, and impaired microcirculation in the intestine. Preclinical studies by our group have led to the discovery of remote ischemic conditioning (RIC) as a promising non-invasive intervention in protecting the intestine against ischemia-induced damage during early-stage NEC. RIC involves the administration of brief reversible cycles of ischemia and reperfusion in a limb (similar to taking standard blood pressure measurement) which activate endogenous protective signaling pathways that are conveyed to distant organs such as the intestine. RIC targets the intestinal microcirculation and by improving blood flow to the intestine, reduces the intestinal damage of experimental NEC and prolongs survival. A recent Phase I safety study by our group demonstrated that RIC was safe in preterm infants with NEC. A phase II feasibility randomized controlled trial involving 12 centers in 6 countries is currently underway, to investigate the feasibility of RIC as a treatment for early-stage NEC in preterm neonates. This review provides a brief background on RIC as a therapeutic strategy and summarizes the progression of RIC as a treatment for NEC from preclinical investigation to clinical evaluation.
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Affiliation(s)
- Niloofar Ganji
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - George Biouss
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Stella Sabbatini
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Bo Li
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Carol Lee
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Agostino Pierro
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada; Division of General and Thoracic Surgery, The Hospital for Sick Children, University of Toronto, 1526-555 University Ave, Toronto, ON M5G 1×8, Canada.
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Ortega-Trejo JA, Bobadilla NA. Is Renal Ischemic Preconditioning an Alternative to Ameliorate the Short- and Long-Term Consequences of Acute Kidney Injury? Int J Mol Sci 2023; 24:ijms24098345. [PMID: 37176051 PMCID: PMC10178892 DOI: 10.3390/ijms24098345] [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: 03/14/2023] [Revised: 04/21/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Acute kidney injury (AKI) is a global health problem and has recently been recognized as a risk factor for developing chronic kidney disease (CKD). Unfortunately, there are no effective treatments to reduce or prevent AKI, which results in high morbidity and mortality rates. Ischemic preconditioning (IPC) has emerged as a promising strategy to prevent, to the extent possible, renal tissue from AKI. Several studies have used this strategy, which involves short or long cycles of ischemia/reperfusion (IR) prior to a potential fatal ischemic injury. In most of these studies, IPC was effective at reducing renal damage. Since the first study that showed renoprotection due to IPC, several studies have focused on finding the best strategy to activate correctly and efficiently reparative mechanisms, generating different modalities with promising results. In addition, the studies performing remote IPC, by inducing an ischemic process in distant tissues before a renal IR, are also addressed. Here, we review in detail existing studies on IPC strategies for AKI pathophysiology and the proposed triggering mechanisms that have a positive impact on renal function and structure in animal models of AKI and in humans, as well as the prospects and challenges for its clinical application.
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Affiliation(s)
- Juan Antonio Ortega-Trejo
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Norma A Bobadilla
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
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Mei C, Ma T. Roles of isometric contraction training in promoting neuroprotection and angiogenesis after stroke in adult rats. Physiol Res 2022; 71:425-438. [PMID: 35616043 DOI: 10.33549/physiolres.934849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
100 rats were randomly divided into a sham-operated group and middle cerebral artery occlusion (MCAO) modeling groups. The sham group after surgery was observed for 14 days. After MCAO, some rats received isometric contraction training (ICT) which was as follows: an atraumatic tourniquet was placed around left or right hind limb to achieve hind limb ischemia for 5 min, followed by 5 min of reperfusion, 4 cycles for one time, once a day, and five days per week. The MCAO modeling groups included the following four groups: i) a group only received MCAO, and was observed for seven days (MCAO-7d), ii) a group only received MCAO, and was observed for 14 days (MCAO-14d), iii) a group, after MCAO, received ICT for seven days (ICT-7d), and iv) a group, after MCAO, received ICT for 14 days (ICT-14d). Brain infarct area, behavioral outcomes, the number of neurons, apoptosis, cerebral edema and cerebral water content were assessed, respectively. The mRNA expression of vascular endothelial growth factor (VEGF) was assayed with RT-PCR, and protein expression of VEGF was quantified with western blot. compared with MCAO controls, cerebral infarction, neurological deficits and neuronal apoptosis were reduced significantly in the ICT groups, while the number of neurons was increased. Moreover, the mRNA expression of VEGF and protein expression of VEGF were enhanced after 1 and 2 weeks of ICT. ICT may promote angiogenesis and neuroprotection after ischemic stroke and this new remodeling method provide a novel strategy for rehabilitation of stroke patients.
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Affiliation(s)
- C Mei
- Pukou Branch of Jiangsu People's Hospital, Nanjing City, Jiangsu Province, P. R. China.
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Lang JA, Kim J. Remote ischaemic preconditioning - translating cardiovascular benefits to humans. J Physiol 2022; 600:3053-3067. [PMID: 35596644 PMCID: PMC9327506 DOI: 10.1113/jp282568] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 05/17/2022] [Indexed: 11/26/2022] Open
Abstract
Remote ischaemic preconditioning (RIPC), induced by intermittent periods of limb ischaemia and reperfusion, confers cardiac and vascular protection from subsequent ischaemia–reperfusion (IR) injury. Early animal studies reliably demonstrate that RIPC attenuated infarct size and preserved cardiac tissue. However, translating these adaptations to clinical practice in humans has been challenging. Large clinical studies have found inconsistent results with respect to RIPC eliciting IR injury protection or improving clinical outcomes. Follow‐up studies have implicated several factors that potentially affect the efficacy of RIPC in humans such as age, fitness, frequency, disease state and interactions with medications. Thus, realizing the clinical potential for RIPC may require a human experimental model where confounding factors are more effectively controlled and underlying mechanisms can be further elucidated. In this review, we highlight recent experimental findings in the peripheral circulation that have added valuable insight on the mechanisms and clinical benefit of RIPC in humans. Central to this discussion is the critical role of timing (i.e. immediate vs. delayed effects following a single bout of RIPC) and the frequency of RIPC. Limited evidence in humans has demonstrated that repeated bouts of RIPC over several days uniquely improves vascular function beyond that observed with a single bout alone. Since changes in resistance vessel and microvascular function often precede symptoms and diagnosis of cardiovascular disease, repeated bouts of RIPC may be promising as a preclinical intervention to prevent or delay cardiovascular disease progression.
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Affiliation(s)
- James A Lang
- Department of Kinesiology, Iowa State University, Ames, IA, USA
| | - Jahyun Kim
- Department of Kinesiology, California State University Bakersfield, Bakersfield, CA, USA
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Hamarneh A, Ho AFW, Bulluck H, Sivaraman V, Ricciardi F, Nicholas J, Shanahan H, Hardman EA, Wicks P, Ramlall M, Chung R, McGowan J, Cordery R, Lawrence D, Clayton T, Kyle B, Xenou M, Ariti C, Yellon DM, Hausenloy DJ. Negative interaction between nitrates and remote ischemic preconditioning in patients undergoing cardiac surgery: the ERIC-GTN and ERICCA studies. Basic Res Cardiol 2022; 117:31. [PMID: 35727392 PMCID: PMC9213287 DOI: 10.1007/s00395-022-00938-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 05/21/2022] [Accepted: 05/23/2022] [Indexed: 01/31/2023]
Abstract
Remote ischaemic preconditioning (RIPC) using transient limb ischaemia failed to improve clinical outcomes following cardiac surgery and the reasons for this remain unclear. In the ERIC-GTN study, we evaluated whether concomitant nitrate therapy abrogated RIPC cardioprotection. We also undertook a post-hoc analysis of the ERICCA study, to investigate a potential negative interaction between RIPC and nitrates on clinical outcomes following cardiac surgery. In ERIC-GTN, 185 patients undergoing cardiac surgery were randomized to: (1) Control (no RIPC or nitrates); (2) RIPC alone; (3); Nitrates alone; and (4) RIPC + Nitrates. An intravenous infusion of nitrates (glyceryl trinitrate 1 mg/mL solution) was commenced on arrival at the operating theatre at a rate of 2-5 mL/h to maintain a mean arterial pressure between 60 and 70 mmHg and was stopped when the patient was taken off cardiopulmonary bypass. The primary endpoint was peri-operative myocardial injury (PMI) quantified by a 48-h area-under-the-curve high-sensitivity Troponin-T (48 h-AUC-hs-cTnT). In ERICCA, we analysed data for 1502 patients undergoing cardiac surgery to investigate for a potential negative interaction between RIPC and nitrates on clinical outcomes at 12-months. In ERIC-GTN, RIPC alone reduced 48 h-AUC-hs-cTnT by 37.1%, when compared to control (ratio of AUC 0.629 [95% CI 0.413-0.957], p = 0.031), and this cardioprotective effect was abrogated in the presence of nitrates. Treatment with nitrates alone did not reduce 48 h-AUC-hs-cTnT, when compared to control. In ERICCA there was a negative interaction between nitrate use and RIPC for all-cause and cardiovascular mortality at 12-months, and for risk of peri-operative myocardial infarction. RIPC alone reduced the risk of peri-operative myocardial infarction, compared to control, but no significant effect of RIPC was demonstrated for the other outcomes. When RIPC and nitrates were used together they had an adverse impact in patients undergoing cardiac surgery with the presence of nitrates abrogating RIPC-induced cardioprotection and increasing the risk of mortality at 12-months post-cardiac surgery in patients receiving RIPC.
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Affiliation(s)
- Ashraf Hamarneh
- Institute of Cardiovascular Sciences, The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK
| | - Andrew Fu Wah Ho
- Department of Emergency Medicine, Singapore General Hospital, Singapore, Singapore
- Pre-Hospital and Emergency Research Centre, Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore
| | - Heerajnarain Bulluck
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
- Department of Cardiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Vivek Sivaraman
- Institute of Cardiovascular Sciences, The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK
| | - Federico Ricciardi
- Department of Statistical Science, University College London, London, UK
| | - Jennifer Nicholas
- Clinical Trials Unit and Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
| | - Hilary Shanahan
- University College London Hospitals NHS Foundation Trust, London, UK
| | | | - Peter Wicks
- University Hospital Southampton NHS Foundation Trust, London, UK
| | - Manish Ramlall
- Institute of Cardiovascular Sciences, The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK
| | - Robin Chung
- Institute of Cardiovascular Sciences, The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK
| | - John McGowan
- Institute of Cardiovascular Sciences, The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK
| | - Roger Cordery
- Barts Heart Centre, King's College London, London, UK
| | - David Lawrence
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Tim Clayton
- Clinical Trials Unit and Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
| | - Bonnie Kyle
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Maria Xenou
- Institute of Cardiovascular Sciences, The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK
| | - Cono Ariti
- University Hospital of Wales, Heath Park, Cardiff, CF14 4YS, UK
| | - Derek M Yellon
- Institute of Cardiovascular Sciences, The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK
| | - Derek J Hausenloy
- Institute of Cardiovascular Sciences, The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK.
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.
- Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.
- Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taichung City, Taiwan.
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10
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Long YQ, Feng XM, Shan XS, Chen QC, Xia Z, Ji FH, Liu H, Peng K. Remote Ischemic Preconditioning Reduces Acute Kidney Injury After Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Anesth Analg 2021; 134:592-605. [PMID: 34748518 DOI: 10.1213/ane.0000000000005804] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Results from previous studies evaluating the effects of remote ischemic preconditioning (RIPC) on morbidity and mortality after cardiac surgery are inconsistent. This meta-analysis of randomized controlled trials (RCTs) aims to determine whether RIPC improves cardiac and renal outcomes in adults undergoing cardiac surgery. METHODS PubMed, EMBASE, and Cochrane Library were comprehensively searched to identify RCTs comparing RIPC with control in cardiac surgery. The coprimary outcomes were the incidence of postoperative myocardial infarction (MI) and the incidence of postoperative acute kidney injury (AKI). Meta-analyses were performed using a random-effect model. Subgroup analyses were conducted according to volatile only anesthesia versus propofol anesthesia with or without volatiles, high-risk patients versus non-high-risk patients, and Acute Kidney Injury Network (AKIN) or Kidney Disease Improving Global Outcomes (KDIGO) criteria versus other criteria for AKI diagnosis. RESULTS A total of 79 RCTs with 10,814 patients were included. While the incidence of postoperative MI did not differ between the RIPC and control groups (8.2% vs 9.7%; risk ratio [RR] = 0.87, 95% confidence interval [CI], 0.76-1.01, P = .07, I2 = 0%), RIPC significantly reduced the incidence of postoperative AKI (22% vs 24.4%; RR = 0.86, 95% CI, 0.77-0.97, P = .01, I2 = 34%). The subgroup analyses showed that RIPC was associated with a reduced incidence of MI in non-high-risk patients, and that RIPC was associated with a reduced incidence of AKI in volatile only anesthesia, in non-high-risk patients, and in the studies using AKIN or KDIGO criteria for AKI diagnosis. CONCLUSIONS This meta-analysis demonstrates that RIPC reduces the incidence of AKI after cardiac surgery. This renoprotective effect of RIPC is mainly evident during volatile only anesthesia, in non-high-risk patients, and when AKIN or KDIGO criteria used for AKI diagnosis.
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Affiliation(s)
- Yu-Qin Long
- From the Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiao-Mei Feng
- Department of Anesthesiology, University of Utah Health, Salt Lake City, Utah.,Transitional Residency Program, Intermountain Medical Center, Murray, Utah
| | - Xi-Sheng Shan
- From the Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Qing-Cai Chen
- From the Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhengyuan Xia
- Department of Anesthesiology and Pain Medicine, University of California Davis Health, Sacramento, California
| | - Fu-Hai Ji
- From the Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hong Liu
- Department of Anesthesiology and Pain Medicine, University of California Davis Health, Sacramento, California
| | - Ke Peng
- From the Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
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Femminò S, D’Ascenzo F, Ravera F, Comità S, Angelini F, Caccioppo A, Franchin L, Grosso A, Thairi C, Venturelli E, Cavallari C, Penna C, De Ferrari GM, Camussi G, Pagliaro P, Brizzi MF. Percutaneous Coronary Intervention (PCI) Reprograms Circulating Extracellular Vesicles from ACS Patients Impairing Their Cardio-Protective Properties. Int J Mol Sci 2021; 22:ijms221910270. [PMID: 34638611 PMCID: PMC8508604 DOI: 10.3390/ijms221910270] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/14/2021] [Accepted: 09/16/2021] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs) are promising therapeutic tools in the treatment of cardiovascular disorders. We have recently shown that EVs from patients with Acute Coronary Syndrome (ACS) undergoing sham pre-conditioning, before percutaneous coronary intervention (PCI) were cardio-protective, while EVs from patients experiencing remote ischemic pre-conditioning (RIPC) failed to induce protection against ischemia/reperfusion Injury (IRI). No data on EVs from ACS patients recovered after PCI are currently available. Therefore, we herein investigated the cardio-protective properties of EVs, collected after PCI from the same patients. EVs recovered from 30 patients randomly assigned (1:1) to RIPC (EV-RIPC) or sham procedures (EV-naive) (NCT02195726) were characterized by TEM, FACS and Western blot analysis and evaluated for their mRNA content. The impact of EVs on hypoxia/reoxygenation damage and IRI, as well as the cardio-protective signaling pathways, were investigated in vitro (HMEC-1 + H9c2 co-culture) and ex vivo (isolated rat heart). Both EV-naive and EV-RIPC failed to drive cardio-protection both in vitro and ex vivo. Consistently, EV treatment failed to activate the canonical cardio-protective pathways. Specifically, PCI reduced the EV-naive Dusp6 mRNA content, found to be crucial for their cardio-protective action, and upregulated some stress- and cell-cycle-related genes in EV-RIPC. We provide the first evidence that in ACS patients, PCI reprograms the EV cargo, impairing EV-naive cardio-protective properties without improving EV-RIPC functional capability.
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Affiliation(s)
- Saveria Femminò
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.F.); (F.R.); (A.C.); (A.G.); (E.V.); (G.C.)
| | - Fabrizio D’Ascenzo
- Department of Medical Sciences, Division of Cardiology, University of Turin, 10126 Turin, Italy; (F.D.); (F.A.); (L.F.); (G.M.D.F.)
| | - Francesco Ravera
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.F.); (F.R.); (A.C.); (A.G.); (E.V.); (G.C.)
| | - Stefano Comità
- Department of Clinical and Biological Sciences, University of Turin, 10143 Orbassano, Italy; (S.C.); (C.T.); (C.P.); (P.P.)
| | - Filippo Angelini
- Department of Medical Sciences, Division of Cardiology, University of Turin, 10126 Turin, Italy; (F.D.); (F.A.); (L.F.); (G.M.D.F.)
| | - Andrea Caccioppo
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.F.); (F.R.); (A.C.); (A.G.); (E.V.); (G.C.)
| | - Luca Franchin
- Department of Medical Sciences, Division of Cardiology, University of Turin, 10126 Turin, Italy; (F.D.); (F.A.); (L.F.); (G.M.D.F.)
| | - Alberto Grosso
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.F.); (F.R.); (A.C.); (A.G.); (E.V.); (G.C.)
| | - Cecilia Thairi
- Department of Clinical and Biological Sciences, University of Turin, 10143 Orbassano, Italy; (S.C.); (C.T.); (C.P.); (P.P.)
| | - Emilio Venturelli
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.F.); (F.R.); (A.C.); (A.G.); (E.V.); (G.C.)
| | | | - Claudia Penna
- Department of Clinical and Biological Sciences, University of Turin, 10143 Orbassano, Italy; (S.C.); (C.T.); (C.P.); (P.P.)
| | - Gaetano Maria De Ferrari
- Department of Medical Sciences, Division of Cardiology, University of Turin, 10126 Turin, Italy; (F.D.); (F.A.); (L.F.); (G.M.D.F.)
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.F.); (F.R.); (A.C.); (A.G.); (E.V.); (G.C.)
| | - Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Turin, 10143 Orbassano, Italy; (S.C.); (C.T.); (C.P.); (P.P.)
| | - Maria Felice Brizzi
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (S.F.); (F.R.); (A.C.); (A.G.); (E.V.); (G.C.)
- Correspondence: ; Tel.: +39-011-670-6653
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13
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Effect of Repeated Remote Ischemic Preconditioning on Peripheral Arterial Disease in Patients Suffering from Intermittent Claudication. Cardiovasc Ther 2020; 2019:9592378. [PMID: 31897086 PMCID: PMC6925938 DOI: 10.1155/2019/9592378] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 09/04/2019] [Accepted: 09/24/2019] [Indexed: 12/15/2022] Open
Abstract
Background/Objective Intermittent claudication (IC) is the symptom of peripheral artery disease (PAD) and causes functional disability. Remote ischemic preconditioning (RIPC), is a phenomenon in which a short period of sub-critical ischemia, protects tissues against ischemia/reperfusion/injury. We considered to test the hypothesis that RIPC in PAD patients suffering from IC would increase muscle resistance to ischemia and thus improve walking-capacity. Materials/Methods A total of 63 patients with proven-IC underwent two treadmill tests (graded treadmill protocol) with a 28-day interval in between. Patients were consecutively assigned for the non/RIPC-group and RIPC-group procedure one by one. Patients received 5-cycles of alternating 5-minute inflation and 5-minute deflation of blood-pressure cuffs on nondominant upper-limb every day for four weeks. Initial claudication distance (ICD), total walking distance (TWD) and time to relief of claudication (TRC) were recorded during procedure. Results Patients receiving-RIPC exhibited a marked increase in ICD and TWD between basal and last tests: 209.1 ± 15.4 m vs. 226 ± 15.0 m and 368.8 ± 21.0 m vs. 394 ± 19.9 m, respectively (p < 0.001). In addition, patients receiving-RIPC represented a significant decrease in TRC between basal and last tests: 7.8 ± 1.3 min vs. 6.4 ± 1.1 min, respectively (p < 0.001). Patients not receiving-RIPC did not exhibit improvement in ICD, TWD, and TRC between basal and last tests: 205.2 ± 12.1 min vs. 207.4 ± 9.9 min, 366.5 ± 24.2 min vs. 369.4 ± 23.2 min and 7.9 ± 1.4 min vs. 7.7 ± 1.3 min, respectively (p > 0.05). Conclusion A significant increase in ICD and TWD were observed in last/treadmill test in RIPC-group. In addition, a significant decrease in TRC was observed in last/treadmill test in RIPC-group. In non/RIPC-group, no improvement was observed in ICD, TWD and TRC.
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Gumbert SD, Kork F, Jackson ML, Vanga N, Ghebremichael SJ, Wang CY, Eltzschig HK. Perioperative Acute Kidney Injury. Anesthesiology 2020; 132:180-204. [PMID: 31687986 PMCID: PMC10924686 DOI: 10.1097/aln.0000000000002968] [Citation(s) in RCA: 179] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Perioperative organ injury is among the leading causes of morbidity and mortality of surgical patients. Among different types of perioperative organ injury, acute kidney injury occurs particularly frequently and has an exceptionally detrimental effect on surgical outcomes. Currently, acute kidney injury is most commonly diagnosed by assessing increases in serum creatinine concentration or decreased urine output. Recently, novel biomarkers have become a focus of translational research for improving timely detection and prognosis for acute kidney injury. However, specificity and timing of biomarker release continue to present challenges to their integration into existing diagnostic regimens. Despite many clinical trials using various pharmacologic or nonpharmacologic interventions, reliable means to prevent or reverse acute kidney injury are still lacking. Nevertheless, several recent randomized multicenter trials provide new insights into renal replacement strategies, composition of intravenous fluid replacement, goal-directed fluid therapy, or remote ischemic preconditioning in their impact on perioperative acute kidney injury. This review provides an update on the latest progress toward the understanding of disease mechanism, diagnosis, and managing perioperative acute kidney injury, as well as highlights areas of ongoing research efforts for preventing and treating acute kidney injury in surgical patients.
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Affiliation(s)
- Sam D. Gumbert
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
| | - Felix Kork
- Department of Anaesthesiology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Maisie L. Jackson
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
| | - Naveen Vanga
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
| | - Semhar J. Ghebremichael
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
| | - Christy Y. Wang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
| | - Holger K. Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
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Cheskes S, Koh M, Turner L, Heslegrave R, Verbeek R, Dorian P, Scales DC, Singh B, Amlani S, Natarajan M, Morrison LJ, Kakar P, Nowickyj R, Lawrence M, Cameron J, Ko DT. Field Implementation of Remote Ischemic Conditioning in ST-Segment-Elevation Myocardial Infarction: The FIRST Study. Can J Cardiol 2019; 36:1278-1288. [PMID: 32305146 DOI: 10.1016/j.cjca.2019.11.029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 11/05/2019] [Accepted: 11/22/2019] [Indexed: 10/25/2022] Open
Abstract
BACKGROUND Remote ischemic conditioning (RIC) is a noninvasive therapeutic strategy that uses brief cycles of blood pressure cuff inflation and deflation to protect the myocardium against ischemia-reperfusion injury. We sought to compare major adverse cardiovascular events (MACE) for patients who received RIC before PCI for ST-segment-elevation myocardial infarction (STEMI) compared with standard care. METHODS We conducted a pre- and postimplementation study. In the preimplementation phase, STEMI patients were taken directly to the PCI lab. After implementation, STEMI patients received 4 cycles of RIC by paramedics or emergency department staff before PCI. The primary outcome was MACE at 90 days. Secondary outcomes included MACE at 30, 60, and 180 days. Inverse probability of treatment weighting using propensity scores estimated causal effects independent from baseline covariables. RESULTS A total of 1667 (866 preimplementation, 801 postimplementation) patients were included. In the preimplementation phase, 13.4% had MACE at 90 days compared with 11.8% in the postimplementation phase (odds ratio [OR] 0.86, 95% CI 0.62-1.21). There were no significant differences in MACE at 30, 60, and 180 days. Patients presenting with cardiogenic shock or cardiac arrest before PCI were less likely to have MACE at 90 days (42.7% pre vs 27.8% post) if they received RIC before PCI (OR 0.52, 95% CI 0.27-0.98). CONCLUSIONS A strategy of RIC before PCI for STEMI did not reduce 90-day MACE. Future research should explore the impact of RIC before PCI for longer-term clinical outcomes and for patients presenting with cardiogenic shock or cardiac arrest.
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Affiliation(s)
- Sheldon Cheskes
- Division of Emergency Medicine, Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada; Sunnybrook Centre for Prehospital Medicine, Toronto, Ontario, Canada; Li Ka Shing Knowledge Institute, St Michaels Hospital, Toronto, Ontario, Canada.
| | - Maria Koh
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
| | - Linda Turner
- Sunnybrook Centre for Prehospital Medicine, Toronto, Ontario, Canada
| | | | - Richard Verbeek
- Sunnybrook Centre for Prehospital Medicine, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Paul Dorian
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada; St Michaels Hospital, Toronto, Ontario, Canada
| | - Damon C Scales
- Li Ka Shing Knowledge Institute, St Michaels Hospital, Toronto, Ontario, Canada; Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Bob Singh
- Trillium Health Partners, Mississauga, Ontario, Canada
| | - Shy Amlani
- William Osler Health System, Brampton, Ontario, Canada
| | | | - Laurie J Morrison
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Priya Kakar
- Peel Regional Paramedic Service, Ontario, Canada
| | | | | | | | - Dennis T Ko
- Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
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16
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Deferrari G, Bonanni A, Bruschi M, Alicino C, Signori A. Remote ischaemic preconditioning for renal and cardiac protection in adult patients undergoing cardiac surgery with cardiopulmonary bypass: systematic review and meta-analysis of randomized controlled trials. Nephrol Dial Transplant 2019; 33:813-824. [PMID: 28992285 DOI: 10.1093/ndt/gfx210] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 04/28/2017] [Indexed: 12/20/2022] Open
Abstract
Background The main aim of this systematic review was to assess whether remote ischaemic preconditioning (RIPC) protects kidneys and the heart in cardiac surgery with cardiopulmonary bypass (CPB) and to investigate a possible role of anaesthetic agents. Methods Randomized clinical trials (RCTs) on the effects of RIPC through limb ischaemia in adult patients undergoing cardiac surgery with CPB were searched (1965-October 2016) in PubMed, Cochrane Library and article reference lists. A random effects model on standardized mean difference (SMD) for continuous outcomes and the Peto odds ratio (OR) for dichotomous outcomes were used to meta-analyse data. Subgroup analyses to evaluate the effects of different anaesthetic regimens were pre-planned. Results Thirty-three RCTs (5999 participants) were included. In the whole group, RIPC did not significantly reduce the incidence of acute kidney injury (AKI), acute myocardial infarction, atrial fibrillation, mortality or length of intensive care unit (ICU) and hospital stays. On the contrary, RIPC significantly reduced the area under the curve for myocardial injury biomarkers (MIBs) {SMD -0.37 [95% confidence interval (CI) -0.53 to - 0.21]} and the composite endpoint incidence [OR 0.85 (95% CI 0.74-0.97)]. In the volatile anaesthetic group, RIPC significantly reduced AKI incidence [OR 0.57 (95% CI 0.41-0.79)] and marginally reduced ICU stay. Conversely, except for MIBs, RIPC had fewer non-significant effects under propofol with or without volatile anaesthetics. Conclusions RIPC did not consistently reduce morbidity and mortality in adults undergoing cardiac surgery with CPB. In the subgroup on volatile anaesthetics only, RIPC markedly and significantly reduced the incidence of AKI and composite endpoint as well as myocardial injury.
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Affiliation(s)
- Giacomo Deferrari
- Department of Cardionephrology, Istituto Clinico Di Alta Specialità (ICLAS), Rapallo (GE), Italy.,Department of Internal Medicine (Di.MI), University of Genoa, Genoa, Italy
| | - Alice Bonanni
- Department of Cardionephrology, Istituto Clinico Di Alta Specialità (ICLAS), Rapallo (GE), Italy.,Division of Nephrology, Dialysis and Transplantation and Laboratory on Pathophysiology of Uremia, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Maurizio Bruschi
- Division of Nephrology, Dialysis and Transplantation and Laboratory on Pathophysiology of Uremia, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Cristiano Alicino
- Department of Health Science (Di.S.Sal), University of Genoa, Genoa, Italy
| | - Alessio Signori
- Department of Health Science (Di.S.Sal), University of Genoa, Genoa, Italy
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17
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Deja MA, Piekarska M, Malinowski M, Wiaderkiewicz R, Czekaj P, Machej L, Węglarzy A, Kowalówka A, Kołodziej T, Czech E, Plewka D, Mizia M, Latusek T, Szurlej B. Can human myocardium be remotely preconditioned? The results of a randomized controlled trial. Eur J Cardiothorac Surg 2019; 55:1086-1094. [PMID: 30649238 DOI: 10.1093/ejcts/ezy441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 11/02/2018] [Accepted: 11/17/2018] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES No experimental study has shown that the myocardium of a remotely preconditioned patient is more resistant to a standardized ischaemic/hypoxic insult. METHODS This was a single-centre randomized (1:1), double-blinded, sham-controlled, parallel-group study. Patients referred for elective coronary bypass surgery were allocated to either remote ischaemic preconditioning (3 cycles of 5-min ischaemia/5-min reperfusion of the right arm using a blood pressure cuff inflated to 200 mmHg) or sham intervention. One hundred and thirty-four patients were recruited, of whom 10 dropped out, and 4 were excluded from the per-protocol analysis. The right atrial trabecula harvested on cannulation for cardiopulmonary bypass was subjected to 60 min of simulated ischaemia and 120 min of reoxygenation in an isolated organ experiment. Postoperative troponin T release and haemodynamics were assessed in an in vivo study. RESULTS The atrial trabeculae obtained from remotely preconditioned patients recovered 41.9% (36.3-48.3) of the initial contraction force, whereas those from non-preconditioned patients recovered 45.9% (39.1-53.7) (P = 0.399). Overall, the content of cleaved poly (ADP ribose) polymerase in the right atrial muscle increased from 9.4% (6.0-13.5) to 19.1% (13.2-23.8) (P < 0.001) after 1 h of ischaemia and 2 h of reperfusion in vitro. The amount of activated Caspase 3 and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells also significantly increased. No difference was observed between the remotely preconditioned and sham-treated myocardium. In the in vivo trial, the area under the curve for postoperative concentration of troponin T over 72 h was 16.4 ng⋅h/ml (95% confidence interval 14.2-18.9) for the remote ischaemic preconditioning and 15.5 ng⋅h/ml (13.4-17.9) for the control group in the intention-to-treat analysis. This translated into an area under the curve ratio of 1.06 (0.86-1.30; P = 0.586). CONCLUSIONS Remote ischaemic preconditioning with 3 cycles of 5-min ischaemia/reperfusion of the upper limb before cardiac surgery does not make human myocardium more resistant to ischaemia/reperfusion injury. CLINICAL TRIAL REGISTRATION NUMBER NCT01994707.
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Affiliation(s)
- Marek A Deja
- Department of Cardiac Surgery, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.,Department of Cardiac Surgery, Upper-Silesian Heart Center, Katowice, Poland
| | - Magda Piekarska
- Department of Cardiac Surgery, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.,Department of Cardiac Surgery, Upper-Silesian Heart Center, Katowice, Poland
| | - Marcin Malinowski
- Department of Cardiac Surgery, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.,Department of Cardiac Surgery, Upper-Silesian Heart Center, Katowice, Poland
| | - Ryszard Wiaderkiewicz
- Department of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Piotr Czekaj
- Department of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Leszek Machej
- Department of Anesthesia and Intensive Care Nursing, School of Health Sciences, Medical University of Silesia, Katowice, Poland
| | - Andrzej Węglarzy
- Department of Cardiac Anesthesia, Upper-Silesian Heart Center, Katowice, Poland
| | - Adam Kowalówka
- Department of Cardiac Surgery, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.,Department of Cardiac Surgery, Upper-Silesian Heart Center, Katowice, Poland
| | - Tadeusz Kołodziej
- Department of Cardiac Surgery, Upper-Silesian Heart Center, Katowice, Poland
| | - Ewa Czech
- Department of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Danuta Plewka
- Department of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Magdalena Mizia
- 1 Department of Cardiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Tomasz Latusek
- Department of Cardiac Surgery, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Bartosz Szurlej
- Department of Cardiac Surgery, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
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Jin X, Wang L, Li L, Zhao X. Protective effect of remote ischemic pre-conditioning on patients undergoing cardiac bypass valve replacement surgery: A randomized controlled trial. Exp Ther Med 2019; 17:2099-2106. [PMID: 30867697 PMCID: PMC6396008 DOI: 10.3892/etm.2019.7192] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 12/28/2018] [Indexed: 12/18/2022] Open
Abstract
Remote ischemic pre-conditioning (RIPC) may have a protective effect on myocardial injury associated with cardiac bypass surgery (CPB). The objective of the present study was to investigate the effect of RIPC on ischemia/reperfusion (I/R) injury and to assess the underlying mechanisms. A total of 241 patients who underwent valve replacement were randomly assigned to receive either RIPC (n=121) or control group (n=120). The primary endpoint was peri-operative myocardial injury (PMI), which was determined by serum Highly sensitive cardiac troponin T (hsTnT). The secondary endpoint was the blood gas indexes, acute lung injury and length of intensive care unit stay, length of hospital stay and major adverse cardiovascular events. The results indicated that in comparison with control group, RIPC treatment reduced the levels of hsTnT at 6 and 24 h post-CPB (P<0.001), as well as the alveolar-arterial oxygen pressure difference and respiratory index after CPB. Furthermore, RIPC reduced the incidence of acute lung injury by 15.3% (54.1% in the control group vs. 41.3% in the RIPC group, P=0.053). It was indicated that RIPC provided myocardial and pulmonary protection during CPB. In addition, the length of the intensive care unit and hospital stay was reduced by RIPC. Mechanistic investigation revealed a reduced content of soluble intercellular adhesion molecule-1, endothelin-1 and malondialdehyde, as well as elevated levels of nitric oxide in the RIPC group compared with those in the control group. This indicated that RIPC protected against I/R injury associated with CPB through reducing the inflammatory response and oxidative damage, as well as improving pulmonary vascular tension. In conclusion, RIPC reduced myocardial and pulmonary injury associated with CPB. This protective effect may be associated with the inhibition of the inflammatory response and oxidative injury. The present study proved the efficiency of this approach in reducing ischemia/reperfusion injury associated with cardiac surgery. Clinical trial registry no. ChiCTR1800015393.
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Affiliation(s)
- Xiuling Jin
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Liangrong Wang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Liling Li
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiyue Zhao
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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19
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Bagheri S, Shahbazi S, Shafa M, Borhani-Haghighi A, Kiani M, Sagheb MM. The Effect of Remote Ischemic Preconditioning on the Incidence of Acute Kidney Injury in Patients Undergoing Coronary Artery Bypass Graft Surgery: A Randomized Controlled Trial. IRANIAN JOURNAL OF MEDICAL SCIENCES 2018; 43:587-595. [PMID: 30510335 PMCID: PMC6230941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Remote ischemic preconditioning (RIPC) protects other organs from subsequent lethal ischemic injury, but uncertainty remains. We investigated if RIPC could prevent acute kidney injury (AKI) in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS This parallel-group, double-blind, randomized, controlled trial was done on adults undergoing elective or urgent on-pump CABG surgery from 2013 to 2017 in Shiraz, Iran. Patients were allocated to RIPC or control groups through permuted blocking. The patients in the RIPC group received three cycles of 5 min ischemia and 5 min reperfusion in the upper arm after induction of anesthesia. We placed an uninflated cuff on the arm for 30 min in the control group. The study primary endpoint was an incidence of AKI. Secondary endpoints included short-term clinical outcomes. We compared categorical and continuous variables using Pearson χ2 and unpaired t tests, respectively. P<0.05 was considered significant. RESULTS of the 180 patients randomized to RIPC (n=90) and control (n=90) groups, 87 patients in the RIPC and 90 patients in the control group were included in the analysis. There was no significant difference in the incidence of AKI between the groups (38 patients [43.7%] in the RIPC group and 41 patients [45.6%] in the control group; relative risk, 0.96; 95% confidence interval, 0.69 to 1.33; P=0.80). No significant differences were seen regarding secondary endpoints such as postoperative liver function, atrial fibrillation, and inpatient mortality. CONCLUSION RIPC did not reduce the incidence of AKI, neither did it improve short-term clinical outcomes in patients undergoing on-pump CABG surgery. Trial Registration Number: IRCT2017110537254N1.
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Affiliation(s)
- Sina Bagheri
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shahrbanoo Shahbazi
- Anesthesiology and Critical Care Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Masih Shafa
- Department of Cardiac Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mahsa Kiani
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Mahdi Sagheb
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Majumder A, Singh M, George AK, Homme RP, Laha A, Tyagi SC. Remote ischemic conditioning as a cytoprotective strategy in vasculopathies during hyperhomocysteinemia: An emerging research perspective. J Cell Biochem 2018; 120:77-92. [PMID: 30272816 DOI: 10.1002/jcb.27603] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 08/07/2018] [Indexed: 12/29/2022]
Abstract
Higher levels of nonprotein amino acid homocysteine (Hcy), that is, hyperhomocysteinemia (HHcy) (~5% of general population) has been associated with severe vasculopathies in different organs; however, precise molecular mechanism(s) as to how HHcy plays havoc with body's vascular networks are largely unknown. Interventional modalities have not proven beneficial to counter multifactorial HHcy's effects on the vascular system. An ancient Indian form of exercise called 'yoga' causes transient ischemia as a result of various body postures however the cellular mechanisms are not clear. We discuss a novel perspective wherein we argue that application of remote ischemic conditioning (RIC) could, in fact, deliver anticipated results to patients who are suffering from chronic vascular dysfunction due to HHcy. RIC is the mechanistic phenomenon whereby brief episodes of ischemia-reperfusion events are applied to distant tissues/organs; that could potentially offer a powerful tool in mitigating chronic lethal ischemia in target organs during HHcy condition via simultaneous reduction of inflammation, oxidative and endoplasmic reticulum stress, extracellular matrix remodeling, fibrosis, and angiogenesis. We opine that during ischemic conditioning our organs cross talk by releasing cellular messengers in the form of exosomes containing messenger RNAs, circular RNAs, anti-pyroptotic factors, protective cytokines like musclin, transcription factors, small molecules, anti-inflammatory, antiapoptotic factors, antioxidants, and vasoactive gases. All these could help mobilize the bone marrow-derived stem cells (having tissue healing properties) to target organs. In that context, we argue that RIC could certainly play a savior's role in an unfortunate ischemic or adverse event in people who have higher levels of the circulating Hcy in their systems.
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Affiliation(s)
- Avisek Majumder
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.,Department of Biochemistry and Molecular Genetics, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Mahavir Singh
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.,Eye and Vision Science Laboratory, University of Louisville, Louisville, Kentucky
| | - Akash K George
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.,Eye and Vision Science Laboratory, University of Louisville, Louisville, Kentucky
| | - Rubens Petit Homme
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.,Eye and Vision Science Laboratory, University of Louisville, Louisville, Kentucky
| | - Anwesha Laha
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Suresh C Tyagi
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky
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21
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Hausenloy DJ, Botker HE, Engstrom T, Erlinge D, Heusch G, Ibanez B, Kloner RA, Ovize M, Yellon DM, Garcia-Dorado D. Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations. Eur Heart J 2018; 38:935-941. [PMID: 27118196 PMCID: PMC5381598 DOI: 10.1093/eurheartj/ehw145] [Citation(s) in RCA: 157] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 03/15/2016] [Indexed: 02/07/2023] Open
Affiliation(s)
- Derek J Hausenloy
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore.,The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, London, UK.,National Institute of Health Research University College London Hospitals Biomedical Research Centre, London W1T 7DN, UK
| | - Hans Erik Botker
- Department of Cardiology, Aarhus University Hospital Skejby, DK-8200 Aarhus N, Denmark
| | - Thomas Engstrom
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - David Erlinge
- Department of Cardiology, Lund University, Lund, Sweden
| | - Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
| | - Borja Ibanez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.,IIS-Fundación Jiménez Díaz Hospital, Madrid, Spain
| | - Robert A Kloner
- Huntington Medical Research Institutes, Pasadena, CA, USA.,Division of Cardiovascular Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Michel Ovize
- Explorations Fonctionnelles Cardiovasculaires, Hôpital Louis Pradel, Lyon, France.,UMR 1060 (CarMeN), Université Claude Bernard, Lyon, France
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, London, UK.,National Institute of Health Research University College London Hospitals Biomedical Research Centre, London W1T 7DN, UK
| | - David Garcia-Dorado
- Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma, Pg Vall d'Hebron 119-129, 08035 Barcelona, Spain
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22
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Bøtker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femminò S, García-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhäuser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schlüter KD, Schulz R, Skyschally A, Wilder C, Yellon DM, Ferdinandy P, Heusch G. Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol 2018; 113:39. [PMID: 30120595 PMCID: PMC6105267 DOI: 10.1007/s00395-018-0696-8] [Citation(s) in RCA: 335] [Impact Index Per Article: 47.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/18/2018] [Accepted: 08/03/2018] [Indexed: 02/07/2023]
Affiliation(s)
- Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital, Palle-Juul Jensens Boulevard 99, 8200, Aarhus N, Denmark.
| | - Derek Hausenloy
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
- The National Institute of Health Research, University College London Hospitals Biomedial Research Centre, Research and Development, London, UK
- National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore
- Yon Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, 8 College Road, Singapore, 169857, Singapore
| | - Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Salvatore Antonucci
- Department of Biomedical Sciences, CNR Institute of Neuroscience, University of Padova, Via Ugo Bassi 58/B, 35121, Padua, Italy
| | - Kerstin Boengler
- Institute for Physiology, Justus-Liebig University Giessen, Giessen, Germany
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Soni Deshwal
- Department of Biomedical Sciences, CNR Institute of Neuroscience, University of Padova, Via Ugo Bassi 58/B, 35121, Padua, Italy
| | - Yvan Devaux
- Cardiovascular Research Unit, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Fabio Di Lisa
- Department of Biomedical Sciences, CNR Institute of Neuroscience, University of Padova, Via Ugo Bassi 58/B, 35121, Padua, Italy
| | - Moises Di Sante
- Department of Biomedical Sciences, CNR Institute of Neuroscience, University of Padova, Via Ugo Bassi 58/B, 35121, Padua, Italy
| | - Panagiotis Efentakis
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Saveria Femminò
- Department of Clinical and Biological Sciences, University of Torino, Turin, Italy
| | - David García-Dorado
- Experimental Cardiology, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain
| | - Zoltán Giricz
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - Borja Ibanez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), IIS-Fundación Jiménez Díaz, CIBERCV, Madrid, Spain
| | - Efstathios Iliodromitis
- Second Department of Cardiology, Faculty of Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Nina Kaludercic
- Department of Biomedical Sciences, CNR Institute of Neuroscience, University of Padova, Via Ugo Bassi 58/B, 35121, Padua, Italy
| | - Petra Kleinbongard
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
| | - Markus Neuhäuser
- Department of Mathematics and Technology, Koblenz University of Applied Science, Remagen, Germany
- Institute for Medical Informatics, Biometry, and Epidemiology, University Hospital Essen, Essen, Germany
| | - Michel Ovize
- Explorations Fonctionnelles Cardiovasculaires, Hôpital Louis Pradel, Lyon, France
- UMR, 1060 (CarMeN), Université Claude Bernard, Lyon1, Villeurbanne, France
| | - Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Torino, Turin, Italy
| | - Michael Rahbek-Schmidt
- Department of Cardiology, Aarhus University Hospital, Palle-Juul Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Marisol Ruiz-Meana
- Experimental Cardiology, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain
| | | | - Rainer Schulz
- Institute for Physiology, Justus-Liebig University Giessen, Giessen, Germany
| | - Andreas Skyschally
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
| | - Catherine Wilder
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Peter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany.
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23
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Zhou D, Ding J, Ya J, Pan L, Wang Y, Ji X, Meng R. Remote ischemic conditioning: a promising therapeutic intervention for multi-organ protection. Aging (Albany NY) 2018; 10:1825-1855. [PMID: 30115811 PMCID: PMC6128414 DOI: 10.18632/aging.101527] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Accepted: 08/10/2018] [Indexed: 12/21/2022]
Abstract
Despite decades of formidable exploration, multi-organ ischemia-reperfusion injury (IRI) encountered, particularly amongst elderly patients with clinical scenarios, such as age-related arteriosclerotic vascular disease, heart surgery and organ transplantation, is still an unsettled conundrum that besets clinicians. Remote ischemic conditioning (RIC), delivered via transient, repetitive noninvasive IR interventions to distant organs or tissues, is regarded as an innovative approach against IRI. Based on the available evidence, RIC holds the potential of affording protection to multiple organs or tissues, which include not only the heart and brain, but also others that are likely susceptible to IRI, such as the kidney, lung, liver and skin. Neuronal and humoral signaling pathways appear to play requisite roles in the mechanisms of RIC-related beneficial effects, and these pathways also display inseparable interactions with each other. So far, several hurdles lying ahead of clinical translation that remain to be settled, such as establishment of biomarkers, modification of RIC regimen, and deep understanding of underlying minutiae through which RIC exerts its powerful function. As this approach has garnered an increasing interest, herein, we aim to encapsulate an overview of the basic concept and postulated protective mechanisms of RIC, highlight the main findings from proof-of-concept clinical studies in various clinical scenarios, and also to discuss potential obstacles that remain to be conquered. More well designed and comprehensive experimental work or clinical trials are warranted in future research to confirm whether RIC could be utilized as a non-invasive, inexpensive and efficient adjunct therapeutic intervention method for multi-organ protection.
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Affiliation(s)
- Da Zhou
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
- Equal contribution
| | - Jiayue Ding
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
- Equal contribution
| | - Jingyuan Ya
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Liqun Pan
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Yuan Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Xunming Ji
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Ran Meng
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Department of China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Geriatric Disorders, Beijing, China
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24
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Xie J, Zhang X, Xu J, Zhang Z, Klingensmith NJ, Liu S, Pan C, Yang Y, Qiu H. Effect of Remote Ischemic Preconditioning on Outcomes in Adult Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Studies. Anesth Analg 2018; 127:30-38. [PMID: 29210794 DOI: 10.1213/ane.0000000000002674] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Remote ischemic preconditioning (RIPC) has been demonstrated to prevent organ dysfunction in cardiac surgery patients. However, recent large, prospective, multicenter, randomized controlled trials (RCTs) had controversial results. Thus, a meta-analysis of RCTs was performed to investigate whether RIPC can reduce the incidence of acute myocardial infarction (AMI), acute kidney injury (AKI), and mortality in adult cardiac surgery patients. METHODS Study data were collected from Medline, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. RCTs involving the effect of RIPC on organ protection in cardiac surgery patients, which reported the concentration or total release of creatine kinase-myocardial band, troponin I/troponin T (TNI/TNT) after operation, or the incidence of AMI, AKI, or mortality, were selected. Two reviewers independently extracted data using a standardized data extraction protocol where TNI or TNT concentrations; total TNI released after cardiac surgery; and the incidence of AKI, AMI, and mortality were recorded. Review Manager 5.3 software was used to analyze the data. RESULTS Thirty trials, including 7036 patients were included in the analyses. RIPC significantly decreased the concentration of TNI/TNT (standard mean difference [SMD], -0.25 ng/mL; 95% confidence interval [CI], -0.41 to -0.048 ng/mL; P = .004), creatine kinase-myocardial band (SMD, -0.22; 95% CI, -0.07-0.35 ng/mL; P = .46), and the total TNI/TNT release (SMD, -0.49 ng/mL; 95% CI, -0.93 to -0.55 ng/mL; P = .03) in cardiac surgery patients after a procedure. However, RIPC could not reduce the incidence of AMI (relative risk, 0.89; 95% CI, 0.70-1.13; P = .34) and AKI (relative risk, 0.88; 95% CI, 0.72-1.06; P = .18), and there was also no effect of RIPC on mortality in adult cardiac surgery patients. Interestingly, subgroup analysis showed that RIPC reduced incidence of AKI and mortality of cardiac surgery patients who received volatile agent anesthesia. CONCLUSIONS Our meta-analysis demonstrated that RIPC reduced TNI/TNT release after cardiac surgery. RIPC did not significantly reduce the incidence of AKI, AMI, and mortality. However, RIPC could reduce mortality in patients receiving volatile inhalational agent anesthesia.
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Affiliation(s)
- Jianfeng Xie
- From the Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Xiwen Zhang
- From the Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jingyuan Xu
- From the Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zhongheng Zhang
- Department of Critical Care Medicine, Jinhua Municipal Central Hospital, Jinhua Hospital of Zhejiang University, Zhejiang, China
| | - Nathan J Klingensmith
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia
| | - Songqiao Liu
- From the Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Chun Pan
- From the Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yi Yang
- From the Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Haibo Qiu
- From the Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
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25
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Weber NC, Zuurbier CJ, Hollmann MW. Remote ischaemic preconditioning of the lung: from bench to bedside-are we there yet? J Thorac Dis 2018; 10:98-101. [PMID: 29600031 DOI: 10.21037/jtd.2017.12.75] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Nina C Weber
- Department of Anaesthesiology, Laboratory of Experimental Intensive Care and Anaesthesiology (L.E.I.C.A) Academic Medical Centre (AMC), Amsterdam, the Netherlands
| | - Coert J Zuurbier
- Department of Anaesthesiology, Laboratory of Experimental Intensive Care and Anaesthesiology (L.E.I.C.A) Academic Medical Centre (AMC), Amsterdam, the Netherlands
| | - Markus W Hollmann
- Department of Anaesthesiology, Laboratory of Experimental Intensive Care and Anaesthesiology (L.E.I.C.A) Academic Medical Centre (AMC), Amsterdam, the Netherlands
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26
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Abstract
Rapid admission and acute interventional treatment combined with modern antithrombotic pharmacologic therapy have improved outcomes in patients with ST elevation myocardial infarction. The next major target to further advance outcomes needs to address ischemia-reperfusion injury, which may contribute significantly to the final infarct size and hence mortality and postinfarction heart failure. Mechanical conditioning strategies including local and remote ischemic pre-, per-, and postconditioning have demonstrated consistent cardioprotective capacities in experimental models of acute ischemia-reperfusion injury. Their translation to the clinical scenario has been challenging. At present, the most promising mechanical protection strategy of the heart seems to be remote ischemic conditioning, which increases myocardial salvage beyond acute reperfusion therapy. An additional aspect that has gained recent focus is the potential of extended conditioning strategies to improve physical rehabilitation not only after an acute ischemia-reperfusion event such as acute myocardial infarction and cardiac surgery but also in patients with heart failure. Experimental and preliminary clinical evidence suggests that remote ischemic conditioning may modify cardiac remodeling and additionally enhance skeletal muscle strength therapy to prevent muscle waste, known as an inherent component of a postoperative period and in heart failure. Blood flow restriction exercise and enhanced external counterpulsation may represent cardioprotective corollaries. Combined with exercise, remote ischemic conditioning or, alternatively, blood flow restriction exercise may be of aid in optimizing physical rehabilitation in populations that are not able to perform exercise practice at intensity levels required to promote optimal outcomes.
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Affiliation(s)
- Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital , Aarhus , Denmark
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27
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Park SK, Hur M, Yoo S, Choi JY, Kim WH, Kim JT, Bahk JH. Effect of remote ischaemic preconditioning in patients with ischaemic heart disease undergoing orthopaedic surgery: a randomized controlled trial. Br J Anaesth 2017; 120:198-200. [PMID: 29397131 DOI: 10.1016/j.bja.2017.09.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 08/22/2017] [Accepted: 09/19/2017] [Indexed: 12/27/2022] Open
Affiliation(s)
- S-K Park
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - M Hur
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - S Yoo
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - J-Y Choi
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - W H Kim
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
| | - J-T Kim
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - J-H Bahk
- Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea
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28
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Bromage DI, Pickard JMJ, Rossello X, Ziff OJ, Burke N, Yellon DM, Davidson SM. Remote ischaemic conditioning reduces infarct size in animal in vivo models of ischaemia-reperfusion injury: a systematic review and meta-analysis. Cardiovasc Res 2017; 113:288-297. [PMID: 28028069 PMCID: PMC5408955 DOI: 10.1093/cvr/cvw219] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 09/22/2016] [Indexed: 12/15/2022] Open
Abstract
Aims The potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy. Methods and results Our primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8–26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1–25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization. Conclusions RIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans.
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Affiliation(s)
| | | | | | | | | | - Derek M. Yellon
- Corresponding author. Tel: +44 203 447 9591; fax: +44 203 447 9818, E-mail:
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29
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Yi B, Wang J, Yi D, Zhu Y, Jiang Y, Li Y, Mo S, Liu Y, Rong J. Remote Ischemic Preconditioning and Clinical Outcomes in On-Pump Coronary Artery Bypass Grafting: A Meta-Analysis of 14 Randomized Controlled Trials. Artif Organs 2017; 41:1173-1182. [PMID: 28741665 DOI: 10.1111/aor.12900] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 10/26/2016] [Accepted: 11/01/2016] [Indexed: 12/11/2022]
Abstract
The purpose of this article is to perform the first pooled analysis on remote ischemic preconditioning (RIPC) used for the improvement of clinical outcomes of patients only undergoing on-pump coronary artery bypass grafting (CABG) in randomized controlled trials (RCTs). A systematic search was performed using PubMed, the Cochrane Library, and the Web of Science to identify studies that described the effect of RIPC on postoperative mortality in patients only undergoing on-pump CABG. The outcomes included postoperative mortality, postoperative morbidity (including incidence of myocardial infarction, atrial fibrillation, stroke, acute kidney injury, and renal replacement therapy), mechanical ventilation (MV), intensive care unit length of stay (ICU LOS), and hospital length of stay (HLOS). A total of 14 RCTs (2830 participants) were included. Our meta-analysis found that RIPC failed to reduce the postoperative mortality in patients only undergoing on-pump CABG compared with control individuals (odds ratio, 0.81; 95% confidence interval, [0.40, 1.64]; P = 0.55; I2 = 25%). Moreover, there were no differences in postoperative morbidity, ICU LOS, and HLOS between the two groups. However, MV in the RIPC group was shorter than that in control individuals (standard mean difference, -0.41; 95% confidence interval, [-0.80, -0.01]; P = 0.04; I2 = 73%). The present meta-analysis found that RIPC failed to improve most of clinical outcomes in patients only undergoing on-pump CABG; however, MV was reduced. Adequately powered trials are warranted to provide more evidence in the future.
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Affiliation(s)
- Bin Yi
- Department of Cardiothoracic Surgery, Heart Center, the First Affiliated Hospital, Sun Yat-Sen University, and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China.,Department of Extracorporeal Circulation, Heart Center, the First Affiliated Hospital, Sun Yat-Sen University, and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
| | - Jianhui Wang
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dingwu Yi
- Department of Cardiac Surgery, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Yanling Zhu
- Department of Extracorporeal Circulation, Heart Center, the First Affiliated Hospital, Sun Yat-Sen University, and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
| | - Yumei Jiang
- Department of Extracorporeal Circulation, Heart Center, the First Affiliated Hospital, Sun Yat-Sen University, and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
| | - Yi Li
- Department of Extracorporeal Circulation, Heart Center, the First Affiliated Hospital, Sun Yat-Sen University, and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
| | - Shaoyan Mo
- Department of Extracorporeal Circulation, Heart Center, the First Affiliated Hospital, Sun Yat-Sen University, and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
| | - Yi Liu
- Department of Anesthesiology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jian Rong
- Department of Extracorporeal Circulation, Heart Center, the First Affiliated Hospital, Sun Yat-Sen University, and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
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McLeod SL, Iansavichene A, Cheskes S. Remote Ischemic Perconditioning to Reduce Reperfusion Injury During Acute ST-Segment-Elevation Myocardial Infarction: A Systematic Review and Meta-Analysis. J Am Heart Assoc 2017; 6:JAHA.117.005522. [PMID: 28515120 PMCID: PMC5524098 DOI: 10.1161/jaha.117.005522] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background Remote ischemic conditioning (RIC) is a noninvasive therapeutic strategy that uses brief cycles of blood pressure cuff inflation and deflation to protect the myocardium against ischemia–reperfusion injury. The objective of this systematic review was to determine the impact of RIC on myocardial salvage index, infarct size, and major adverse cardiovascular events when initiated before catheterization. Methods and Results Electronic searches of Medline, Embase, and Cochrane Central Register of Controlled Trials were conducted and reference lists were hand searched. Randomized controlled trials comparing percutaneous coronary intervention (PCI) with and without RIC for patients with ST‐segment–elevation myocardial infarction were included. Two reviewers independently screened abstracts, assessed quality of the studies, and extracted data. Data were pooled using random‐effects models and reported as mean differences and relative risk with 95% confidence intervals. Eleven articles (9 randomized controlled trials) were included with a total of 1220 patients (RIC+PCI=643, PCI=577). Studies with no events were excluded from meta‐analysis. The myocardial salvage index was higher in the RIC+PCI group compared with the PCI group (mean difference: 0.08; 95% confidence interval, 0.02–0.14). Infarct size was reduced in the RIC+PCI group compared with the PCI group (mean difference: −2.46; 95% confidence interval, −4.66 to −0.26). Major adverse cardiovascular events were lower in the RIC+PCI group (9.5%) compared with the PCI group (17.0%; relative risk: 0.57; 95% confidence interval, 0.40–0.82). Conclusions RIC appears to be a promising adjunctive treatment to PCI for the prevention of reperfusion injury in patients with ST‐segment–elevation myocardial infarction; however, additional high‐quality research is required before a change in practice can be considered.
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Affiliation(s)
- Shelley L McLeod
- Division of Emergency Medicine, Department of Family and Community Medicine, University of Toronto, Ontario, Canada.,Schwartz/Reisman Emergency Medicine Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | | | - Sheldon Cheskes
- Division of Emergency Medicine, Department of Family and Community Medicine, University of Toronto, Ontario, Canada .,Sunnybrook Centre for Prehospital Medicine, Toronto, Ontario, Canada.,Rescu, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
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Benstoem C, Stoppe C, Liakopoulos OJ, Ney J, Hasenclever D, Meybohm P, Goetzenich A, Cochrane Heart Group. Remote ischaemic preconditioning for coronary artery bypass grafting (with or without valve surgery). Cochrane Database Syst Rev 2017; 5:CD011719. [PMID: 28475274 PMCID: PMC6481544 DOI: 10.1002/14651858.cd011719.pub3] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Despite substantial improvements in myocardial preservation strategies, coronary artery bypass grafting (CABG) is still associated with severe complications. It has been reported that remote ischaemic preconditioning (RIPC) reduces reperfusion injury in people undergoing cardiac surgery and improves clinical outcome. However, there is a lack of synthesised information and a need to review the current evidence from randomised controlled trials (RCTs). OBJECTIVES To assess the benefits and harms of remote ischaemic preconditioning in people undergoing coronary artery bypass grafting, with or without valve surgery. SEARCH METHODS In May 2016 we searched CENTRAL, MEDLINE, Embase and Web of Science. We also conducted a search of ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP). We also checked reference lists of included studies. We did not apply any language restrictions. SELECTION CRITERIA We included RCTs in which people scheduled for CABG (with or without valve surgery) were randomly assigned to receive RIPC or sham intervention before surgery. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trials for inclusion, extracted data and checked them for accuracy. We calculated mean differences (MDs), standardised mean differences (SMDs) and risk ratios (RR) using a random-effects model. We assessed quality of the trial evidence for all primary outcomes using the GRADE methodology. We completed a 'Risk of bias' assessment for all studies and performed sensitivity analysis by excluding studies judged at high or unclear risk of bias for sequence generation, allocation concealment and incomplete outcome data. We contacted authors for missing data. Our primary endpoints were 1) composite endpoint (including all-cause mortality, non-fatal myocardial infarction or any new stroke, or both) assessed at 30 days after surgery, 2) cardiac troponin T (cTnT, ng/L) at 48 hours and 72 hours, and as area under the curve (AUC) 72 hours (µg/L) after surgery, and 3) cardiac troponin I (cTnI, ng/L) at 48 hours, 72 hours, and as area under the curve (AUC) 72 hours (µg/L) after surgery. MAIN RESULTS We included 29 studies involving 5392 participants (mean age = 64 years, age range 23 to 86 years, 82% male). However, few studies contributed data to meta-analyses due to inconsistency in outcome definition and reporting. In general, risk of bias varied from low to high risk of bias across included studies, and insufficient detail was provided to inform judgement in several cases. The quality of the evidence of key outcomes ranged from moderate to low quality due to the presence of moderate or high statistical heterogeneity, imprecision of results or due to limitations in the design of individual studies.Compared with no RIPC, we found that RIPC has no treatment effect on the rate of the composite endpoint with RR 0.99 (95% confidence interval (CI) 0.78 to 1.25); 2 studies; 2463 participants; moderate-quality evidence. Participants randomised to RIPC showed an equivalent or better effect regarding the amount of cTnT release measured at 72 hours after surgery with SMD -0.32 (95% CI -0.65 to 0.00); 3 studies; 1120 participants; moderate-quality evidence; and expressed as AUC 72 hours with SMD -0.49 (95% CI -0.96 to -0.02); 3 studies; 830 participants; moderate-quality evidence. We found the same result in favour of RIPC for the cTnI release measured at 48 hours with SMD -0.21 (95% CI -0.40 to -0.02); 5 studies; 745 participants; moderate-quality evidence; and measured at 72 hours after surgery with SMD -0.37 (95% CI -0.59 to -0.15); 2 studies; 459 participants; moderate-quality evidence. All other primary outcomes showed no differences between groups (cTnT release measured at 48 hours with SMD -0.14, 95% CI -0.33 to 0.06; 4 studies; 1792 participants; low-quality evidence and cTnI release measured as AUC 72 hours with SMD -0.17, 95% CI -0.48 to 0.14; 2 studies; 159 participants; moderate-quality evidence).We also found no differences between groups for all-cause mortality after 30 days, non-fatal myocardial infarction after 30 days, any new stroke after 30 days, acute renal failure after 30 days, length of stay on the intensive care unit (days), any complications and adverse effects related to ischaemic preconditioning. We did not assess many patient-centred/salutogenic-focused outcomes. AUTHORS' CONCLUSIONS We found no evidence that RIPC has a treatment effect on clinical outcomes (measured as a composite endpoint including all-cause mortality, non-fatal myocardial infarction or any new stroke, or both, assessed at 30 days after surgery). There is moderate-quality evidence that RIPC has no treatment effect on the rate of the composite endpoint including all-cause mortality, non-fatal myocardial infarction or any new stroke assessed at 30 days after surgery, or both. We found moderate-quality evidence that RIPC reduces the cTnT release measured at 72 hours after surgery and expressed as AUC (72 hours). There is moderate-quality evidence that RIPC reduces the amount of cTnI release measured at 48 hours, and measured 72 hours after surgery. Adequately-designed studies, especially focusing on influencing factors, e.g. with regard to anaesthetic management, are encouraged and should systematically analyse the commonly used medications of people with cardiovascular diseases.
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Affiliation(s)
- Carina Benstoem
- University Hospital AachenDepartment of Cardiothoracic SurgeryPauwelsstrasse 30AachenNorth Rhine WestphaliaGermany52074
| | - Christian Stoppe
- RWTH Aachen UniversityDepartment of Intensive Care MedicinePauwelsstrasse 30AachenNorth Rhine WestphaliaGermany52074
| | - Oliver J Liakopoulos
- Heart Center, University of CologneDepartment of Cardiothoracic SurgeryKerpener Str. 62CologneGermany50937
| | - Julia Ney
- University Hospital RWTH AachenDepartment of AnaesthesiologyPauwelsstrasse 30AachenGermany
| | - Dirk Hasenclever
- University of LeipzigInstitute for Medical Informatics, Statistics & Epidemiology (IMISE)Haertelstrasse 16‐18LeipzigGermany
| | - Patrick Meybohm
- University Hospital FrankfurtDepartment of Anaesthesiology, Intensive Care and Pain TherapyTheodor‐Stern‐Kai 7Frankfurt am MainGermany60590
| | - Andreas Goetzenich
- University Hospital AachenDepartment of Cardiothoracic SurgeryPauwelsstrasse 30AachenNorth Rhine WestphaliaGermany52074
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Zhou C, Bulluck H, Fang N, Li L, Hausenloy DJ. Age and Surgical Complexity impact on Renoprotection by Remote Ischemic Preconditioning during Adult Cardiac Surgery: A Meta analysis. Sci Rep 2017; 7:215. [PMID: 28303021 PMCID: PMC5428278 DOI: 10.1038/s41598-017-00308-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 02/16/2017] [Indexed: 01/31/2023] Open
Abstract
We aimed to conduct an up-to-date meta-analysis to comprehensively assess the renoprotective effect of remote ischemic preconditioning (RIPC) in patients undergoing adult cardiac surgery. 21 randomized controlled trials (RCTs) with a total of 6302 patients were selected and identified. Compared with controls, RIPC significantly reduced the incidence of acute kidney injury (AKI) [odds ratio (OR) = 0.79; P = 0.02; I2 = 38%], and in particular, AKI stage I (OR = 0.65; P = 0.01; I2 = 55%). RIPC significantly shortened mechanical ventilation (MV) duration [weighted mean difference (WMD) = −0.79 hours; P = 0.002; I2 = 53%), and reduced intensive care unit (ICU) stay (WMD = −0.23 days; P = 0.07; I2 = 96%). Univariate meta-regression analyses showed that the major sources of heterogeneity for AKI stage I were age (coefficient = 0.06; P = 0.01; adjusted R2 = 0.86) and proportion of complex surgery (coefficient = 0.02; P = 0.03; adjusted R2 = 0.81). Subsequent multivariate regression and subgroup analyses also confirmed these results. The present meta-analysis suggests that RIPC reduces the incidence of AKI in adults undergoing cardiac surgery and this benefit was more pronounced in younger patients undergoing non-complex cardiac surgery. RIPC may also shorten MV duration and ICU stay. Future RCTs tailored for those most likely to benefit from RIPC warrants further investigation.
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Affiliation(s)
- Chenghui Zhou
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Heerajnarain Bulluck
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.,The National Institute of Health Research University College London Hospitals Biomedical Research Centre, London, UK.,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
| | - Nengxin Fang
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Lihuan Li
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
| | - Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.,The National Institute of Health Research University College London Hospitals Biomedical Research Centre, London, UK.,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.,Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, Singapore, Singapore
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Menting TP, Wever KE, Ozdemir‐van Brunschot DMD, Van der Vliet DJA, Rovers MM, Warle MC, Cochrane Kidney and Transplant Group. Ischaemic preconditioning for the reduction of renal ischaemia reperfusion injury. Cochrane Database Syst Rev 2017; 3:CD010777. [PMID: 28258686 PMCID: PMC6464274 DOI: 10.1002/14651858.cd010777.pub2] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Ischaemia reperfusion injury can lead to kidney dysfunction or failure. Ischaemic preconditioning is a short period of deprivation of blood supply to particular organs or tissue, followed by a period of reperfusion. It has the potential to protect kidneys from ischaemia reperfusion injury. OBJECTIVES This review aimed to look at the benefits and harms of local and remote ischaemic preconditioning to reduce ischaemia and reperfusion injury among people with renal ischaemia reperfusion injury. SEARCH METHODS We searched Cochrane Kidney and Transplant's Specialised Register to 5 August 2016 through contact with the Information Specialist using search terms relevant to this review. SELECTION CRITERIA We included all randomised controlled trials measuring kidney function and the role of ischaemic preconditioning in patients undergoing a surgical intervention that induces kidney injury. Kidney transplantation studies were excluded. DATA COLLECTION AND ANALYSIS Studies were assessed for eligibility and quality; data were extracted by two independent authors. We collected basic study characteristics: type of surgery, remote ischaemic preconditioning protocol, type of anaesthesia. We collected primary outcome measurements: serum creatinine and adverse effects to remote ischaemic preconditioning and secondary outcome measurements: acute kidney injury, need for dialysis, neutrophil gelatinase-associated lipocalin, hospital stay and mortality. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS We included 28 studies which randomised a total of 6851 patients. Risk of bias assessment indicated unclear to low risk of bias for most studies. For consistency regarding the direction of effects, continuous outcomes with negative values, and dichotomous outcomes with values less than one favour remote ischaemic preconditioning. Based on high quality evidence, remote ischaemic preconditioning made little or no difference to the reduction of serum creatinine levels at postoperative days one (14 studies, 1022 participants: MD -0.02 mg/dL, 95% CI -0.05 to 0.02; I2 = 21%), two (9 studies, 770 participants: MD -0.04 mg/dL, 95% CI -0.09 to 0.02; I2 = 31%), and three (6 studies, 417 participants: MD -0.05 mg/dL, 95% CI -0.19 to 0.10; I2 = 68%) compared to control.Serious adverse events occurred in four patients receiving remote ischaemic preconditioning by iliac clamping. It is uncertain whether remote ischaemic preconditioning by cuff inflation leads to increased adverse effects compared to control because the certainty of the evidence is low (15 studies, 3993 participants: RR 3.47, 95% CI 0.55 to 21.76; I2 = 0%); only two of 15 studies reported any adverse effects (6/1999 in the remote ischaemic preconditioning group and 1/1994 in the control group), the remaining 13 studies stated no adverse effects were observed in either group.Compared to control, remote ischaemic preconditioning made little or no difference to the need for dialysis (13 studies, 2417 participants: RR 0.85, 95% CI 0.37 to 1.94; I2 = 60%; moderate quality evidence), length of hospital stay (8 studies, 920 participants: MD 0.17 days, 95% CI -0.46 to 0.80; I2 = 49%, high quality evidence), or all-cause mortality (24 studies, 4931 participants: RR 0.86, 95% CI 0.54 to 1.37; I2 = 0%, high quality evidence).Remote ischaemic preconditioning may have slightly improved the incidence of acute kidney injury using either the AKIN (8 studies, 2364 participants: RR 0.76, 95% CI 0.57 to 1.00; I2 = 61%, high quality evidence) or RIFLE criteria (3 studies, 1586 participants: RR 0.91, 95% CI 0.75 to 1.12; I2 = 0%, moderate quality evidence). AUTHORS' CONCLUSIONS Remote ischaemic preconditioning by cuff inflation appears to be a safe method, and probably leads to little or no difference in serum creatinine, adverse effects, need for dialysis, length of hospital stay, death and in the incidence of acute kidney injury. Overall we had moderate-high certainty evidence however the available data does not confirm the efficacy of remote ischaemic preconditioning in reducing renal ischaemia reperfusion injury in patients undergoing major cardiac and vascular surgery in which renal ischaemia reperfusion injury may occur.
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Affiliation(s)
- Theo P Menting
- Radboud University Nijmegen Medical CentreDepartment of SurgeryGeert Grooteplein Zuid 10NijmegenGelderlandNetherlands6525 GA
| | - Kimberley E Wever
- Radboud University Nijmegen Medical CentreDepartment of SurgeryGeert Grooteplein Zuid 10NijmegenGelderlandNetherlands6525 GA
| | - Denise MD Ozdemir‐van Brunschot
- Radboud University Nijmegen Medical CentreDepartment of SurgeryGeert Grooteplein Zuid 10NijmegenGelderlandNetherlands6525 GA
| | - Daan JA Van der Vliet
- Radboud University Nijmegen Medical CentreDepartment of SurgeryGeert Grooteplein Zuid 10NijmegenGelderlandNetherlands6525 GA
| | - Maroeska M Rovers
- Radboud University Nijmegen Medical CentreDepartment of Operating RoomsHp 630, route 631PO Box 9101NijmegenNetherlands6500 HB
| | - Michiel C Warle
- Radboud University Nijmegen Medical CentreDepartment of SurgeryGeert Grooteplein Zuid 10NijmegenGelderlandNetherlands6525 GA
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Pierce B, Bole I, Patel V, Brown DL. Clinical Outcomes of Remote Ischemic Preconditioning Prior to Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc 2017; 6:JAHA.116.004666. [PMID: 28219918 PMCID: PMC5523764 DOI: 10.1161/jaha.116.004666] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background Multiple randomized controlled trials of remote ischemic preconditioning (RIPC) prior to cardiac surgery have failed to demonstrate clinical benefit. The aim of this updated meta‐analysis was to evaluate the effect of RIPC on outcomes following cardiac surgery. Methods and Results Searches of PubMed, Cochrane, EMBASE, and Web of Science databases were performed for 1970 to December 13, 2015. Randomized controlled trials comparing RIPC with a sham procedure prior to cardiac surgery performed with cardiopulmonary bypass were assessed. All‐cause mortality, acute kidney injury (AKI), and myocardial infarction were the primary outcomes of interest. We identified 21 trials that randomized 5262 patients to RIPC or a sham procedure prior to undergoing cardiac surgery. The majority of patients were men (72.6%) and the mean or median age ranged from 42.3 to 76.3 years. Of the 9 trials that evaluated mortality, 188 deaths occurred out of a total of 4210 randomized patients, with 96 deaths occurring in 2098 patients (4.6%) randomized to RIPC and 92 deaths occurring in 2112 patients (4.4%) randomized to a sham control procedure, demonstrating no significant reduction in all‐cause mortality (risk ratio [RR], 0.987; 95% CI, 0.653–1.492, P=0.95). Twelve studies evaluated AKI in 4209 randomized patients. In these studies, AKI was observed in 516 of 2091 patients (24.7%) undergoing RIPC and in 577 of 2118 patients (27.2%) randomized to a sham procedure. RIPC did not result in a significant reduction in AKI (RR, 0.839; 95% CI, 0.703–1.001 [P=0.052]). In 6 studies consisting of 3799 randomized participants, myocardial infarction occurred in 237 of 1891 patients (12.5%) randomized to RIPC and in 282 of 1908 patients (14.8%) randomized to a sham procedure, resulting in no significant reduction in postoperative myocardial infarction (RR, 0.809; 95% CI, 0.615–1.064 [P=0.13]). A subgroup analysis was performed a priori based on previous studies suggesting that propofol may mitigate the protective benefits of RIPC. Three studies randomized patients undergoing cardiac surgery to RIPC or sham procedure in the absence of propofol anesthesia. Most of these patients were men (60.3%) and the mean or median age ranged from 57.0 to 70.6 years. In this propofol‐free subgroup of 434 randomized patients, 71 of 217 patients (32.7%) who underwent RIPC developed AKI compared with 103 of 217 patients (47.5%) treated with a sham procedure. In this cohort, RIPC resulted in a significant reduction in AKI (RR, 0.700; 95% CI, 0.527–0.930 [P=0.014]). In studies of patients who received propofol anesthesia, 445 of 1874 (23.7%) patients randomized to RIPC developed AKI compared with 474 of 1901 (24.9%) who underwent a sham procedure. The RR for AKI was 0.928 (95% CI, 0.781–1.102; P=0.39) for RIPC versus sham. There was no significant interaction between the two subgroups (P=0.098). Conclusions RIPC does not reduce morbidity or mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. In the subgroup of studies in which propofol was not used, a reduction in AKI was seen, suggesting that propofol may interact with the protective effects of RIPC. Future studies should evaluate RIPC in the absence of propofol anesthesia.
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Affiliation(s)
- Brian Pierce
- Hospitalist Division, Washington University School of Medicine, St. Louis, MO
| | - Indra Bole
- Hospitalist Division, Washington University School of Medicine, St. Louis, MO
| | - Vaiibhav Patel
- Hospitalist Division, Washington University School of Medicine, St. Louis, MO
| | - David L Brown
- Cardiovascular Division, Washington University School of Medicine, St. Louis, MO
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Effects of Renal Ischemic Postconditioning on Myocardial Ultrastructural Organization and Myocardial Expression of Bcl-2/Bax in Rabbits. BIOMED RESEARCH INTERNATIONAL 2017; 2016:9349437. [PMID: 28097153 PMCID: PMC5206426 DOI: 10.1155/2016/9349437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 11/10/2016] [Accepted: 11/17/2016] [Indexed: 12/11/2022]
Abstract
We investigated the cardioprotective effect of renal ischemic postconditioning (RI-PostC) and its mechanisms in a rabbit model. Rabbits underwent 60 min of left anterior descending coronary artery occlusion (LADO) and 6 h of reperfusion. The ischemia-reperfusion (IR) group underwent LADO and reperfusion only. In the RI-PostC group, the left renal artery underwent 3 cycles of occlusion for 30 seconds and release for 30 seconds, before the coronary artery was reperfused. In the RI-PostC + GF109203X group, the rabbits received 0.05 mg/kg GF109203X (protein kinase C inhibitor) intravenously for 10 min followed by RI-PostC. Light microscopy and electron microscopy demonstrated that the RI-PostC group showed less pronounced changes, a smaller infarct region, and less apoptosis than the other two groups. Bcl-2 and Bax protein expression did not differ between the IR and RI-PostC + GF109203X groups. However, in the RI-PostC group, Bcl-2 protein expression was significantly higher and Bax protein expression was significantly lower than in the other two groups (P < 0.05). Changes in heart rate and mean arterial pressure were also smaller in the RI-PostC group than in the other two groups. These results indicate that RI-PostC can ameliorate myocardial ischemia-reperfusion injury and increase the Bcl-2/Bax ratio through a mechanism involving protein kinase C.
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Ho PWL, Pang WF, Szeto CC. Remote ischaemic pre-conditioning for the prevention of acute kidney injury. Nephrology (Carlton) 2017; 21:274-85. [PMID: 26370466 DOI: 10.1111/nep.12614] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 08/23/2015] [Accepted: 08/24/2015] [Indexed: 01/02/2023]
Abstract
Acute kidney injury (AKI) is a common complication associated with high morbidity and mortality in hospitalized patients. One potential mechanism underlying renal injury is ischaemia/reperfusion injury (IRI), which attributed the organ damage to the inflammatory and oxidative stress responses induced by a period of renal ischaemia and subsequent reperfusion. Therapeutic strategies that aim at minimizing the effect of IRI on the kidneys may prevent AKI and improve clinical outcomes significantly. In this review, we examine the technique of remote ischaemic preconditioning (rIPC), which has been shown by several trials to confer organ protection by applying transient, brief episodes of ischaemia at a distant site before a larger ischaemic insult. We provide an overview of the current clinical evidence regarding the renoprotective effect of rIPC in the key clinical settings of cardiac or vascular surgery, contrast-induced AKI, pre-existing chronic kidney disease (CKD) and renal transplantation, and discuss key areas for future research.
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Affiliation(s)
- Phoebe Wing-Lam Ho
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Wing-Fai Pang
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Cheuk-Chun Szeto
- Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
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Candilio L, Hausenloy DJ, Yellon DM. Remote Ischemic Conditioning: A Clinical Trial’s Update. J Cardiovasc Pharmacol Ther 2016; 16:304-12. [DOI: 10.1177/1074248411411711] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Coronary artery disease (CAD) is the leading cause of death and disability worldwide, and early and successful restoration of myocardial reperfusion following an ischemic event is the most effective strategy to reduce final infarct size and improve clinical outcome. This process can, however, induce further myocardial damage, namely acute myocardial ischemia-reperfusion injury (IRI) and worsen clinical outcome. Therefore, novel therapeutic strategies are required to protect the myocardium against IRI in patients with CAD. In this regard, the endogenous cardioprotective phenomenon of “ischemic conditioning,” in which the heart is put into a protected state by subjecting it to one or more brief nonlethal episodes of ischemia and reperfusion, has the potential to attenuate myocardial injury during acute IRI. Intriguingly, the heart can be protected in this manner by applying the “ischemic conditioning” stimulus to an organ or tissue remote from the heart (termed remote ischemic conditioning or RIC). Furthermore, the discovery that RIC can be noninvasively applied using a blood pressure cuff on the upper arm to induce brief episodes of nonlethal ischemia and reperfusion in the forearm has greatly facilitated the translation of RIC into the clinical arena. Several recently published proof-of-concept clinical studies have reported encouraging results with RIC, and large multicenter randomized clinical trials are now underway to investigate whether this simple noninvasive and virtually cost-free intervention has the potential to improve clinical outcomes in patients with CAD. In this review article, we provide an update of recently published and ongoing clinical trials in the field of RIC.
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Affiliation(s)
- Luciano Candilio
- The Hatter Cardiovascular Institute, University College London Hospital and Medical School, London, UK
| | - Derek J. Hausenloy
- The Hatter Cardiovascular Institute, University College London Hospital and Medical School, London, UK
| | - Derek M. Yellon
- The Hatter Cardiovascular Institute, University College London Hospital and Medical School, London, UK
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Przyklenk K, Whittaker P. Remote Ischemic Preconditioning: Current Knowledge, Unresolved Questions, and Future Priorities. J Cardiovasc Pharmacol Ther 2016; 16:255-9. [DOI: 10.1177/1074248411409040] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Remote ischemic preconditioning (RIPC) is the phenomenon whereby brief episodes of ischemia–reperfusion applied in distant tissues or organs render the myocardium resistant to a subsequent sustained episode of ischemia. Reduction of infarct size with RIPC has been documented in response to (i) brief antecedent ischemia in a remote coronary vascular bed (intra-cardiac protection); (ii) collection and transfer of coronary effluent from perconditioning “donor” hearts to naive “receptor” hearts (inter-cardiac protection); (iii) brief ischemia applied in skeletal muscle, mesentery, and other organs (interorgan protection); and (iv) remote nociception (“remote PC of trauma”). Moreover, the paradigm has expanded to encompass temporal modifications in the application of the remote stimulus (remote perconditioning and remote postconditioning). Progress has also been made in translating the concept of RIPC to patients undergoing planned ischemic events: evidence for attenuation of cardiac enzyme release with RIPC has been reported after elective abdominal aortic aneurysm repair, angioplasty, and coronary artery bypass graft surgery. However, despite these advances in characterization and clinical application, the mechanisms of RIPC—most notably, the means by which the protective stimulus is communicated to the heart—remain poorly defined and, in all likelihood, are model dependent.
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Affiliation(s)
- Karin Przyklenk
- Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, USA, Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA, Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI, USA
| | - Peter Whittaker
- Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, USA, Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI, USA
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Mudaliar H, Rayner B, Billah M, Kapoor N, Lay W, Dona A, Bhindi R. Remote ischemic preconditioning attenuates EGR-1 expression following myocardial ischemia reperfusion injury through activation of the JAK-STAT pathway. Int J Cardiol 2016; 228:729-741. [PMID: 27888751 DOI: 10.1016/j.ijcard.2016.11.198] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 11/06/2016] [Indexed: 12/26/2022]
Abstract
BACKGROUND/OBJECTIVES Remote ischemic preconditioning (RIPC) protects the myocardium from ischemia/reperfusion (I/R) injury however the molecular pathways involved in cardioprotection are yet to be fully delineated. Transcription factor Early growth response-1 (Egr-1) is a key upstream activator in a variety of cardiovascular diseases. In this study, we elucidated the role of RIPC in modulating the regulation of Egr-1. METHODS This study subjected rats to transient blockade of the left anterior descending (LAD) coronary artery with or without prior RIPC of the hind-limb muscle and thereafter excised the heart 24h following surgical intervention. In vitro, rat cardiac myoblast H9c2 cells were exposed to ischemic preconditioning by subjecting them to 3cycles of alternating nitrogen-flushed hypoxia and normoxia. These preconditioned media were added to recipient H9c2 cells which were then subjected to 30min of hypoxia followed by 30min of normoxia to simulate myocardial I/R injury. Thereafter, the effects of RIPC on cell viability, apoptosis and inflammatory markers were assessed. RESULTS We showed reduced infarct size and suppressed Egr-1 in the heart of rats when RIPC was administered to the hind leg. In vitro, we showed that RIPC improved cell viability, reduced apoptosis and attenuated Egr-1 in recipient cells. CONCLUSIONS Selective inhibition of intracellular signaling pathways confirmed that RIPC increased production of intracellular nitric oxide (NO) and reactive oxygen species (ROS) via activation of the JAK-STAT pathway which then inactivated I/R-induced ERK 1/2 signaling pathways, ultimately leading to the suppression of Egr-1.
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Affiliation(s)
- H Mudaliar
- North Shore Heart Research Foundation, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
| | - B Rayner
- North Shore Heart Research Foundation, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - M Billah
- North Shore Heart Research Foundation, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - N Kapoor
- North Shore Heart Research Foundation, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - W Lay
- North Shore Heart Research Foundation, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - A Dona
- North Shore Heart Research Foundation, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
| | - R Bhindi
- North Shore Heart Research Foundation, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
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Hausenloy DJ, Barrabes JA, Bøtker HE, Davidson SM, Di Lisa F, Downey J, Engstrom T, Ferdinandy P, Carbrera-Fuentes HA, Heusch G, Ibanez B, Iliodromitis EK, Inserte J, Jennings R, Kalia N, Kharbanda R, Lecour S, Marber M, Miura T, Ovize M, Perez-Pinzon MA, Piper HM, Przyklenk K, Schmidt MR, Redington A, Ruiz-Meana M, Vilahur G, Vinten-Johansen J, Yellon DM, Garcia-Dorado D. Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. Basic Res Cardiol 2016; 111:70. [PMID: 27766474 PMCID: PMC5073120 DOI: 10.1007/s00395-016-0588-8] [Citation(s) in RCA: 244] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 10/11/2016] [Indexed: 01/12/2023]
Abstract
To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research.
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Affiliation(s)
- Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London, London, UK. .,The National Institute of Health Research University College London Hospitals Biomedical Research Centre, London, UK. .,Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, 8 College Road, Singapore, 169857, Singapore. .,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.
| | - Jose A Barrabes
- Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma, Barcelona, Spain
| | - Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital Skejby, 8200, Aarhus N, Denmark
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, London, UK
| | - Fabio Di Lisa
- Department of Biomedical Sciences and CNR Institute of Neurosciences, University of Padova, Padua, Italy
| | - James Downey
- Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, USA
| | - Thomas Engstrom
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Hector A Carbrera-Fuentes
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, 8 College Road, Singapore, 169857, Singapore.,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.,Institute for Biochemistry, Medical Faculty Justus-Liebig-University, Giessen, Germany.,Department of Microbiology, Kazan Federal University, Kazan, Russian Federation
| | - Gerd Heusch
- Institute for Pathophysiology, West-German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
| | - Borja Ibanez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.,IIS-Fundación Jiménez Díaz Hospital, Madrid, Spain
| | - Efstathios K Iliodromitis
- 2nd University Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | - Javier Inserte
- Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma, Barcelona, Spain
| | | | - Neena Kalia
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
| | - Rajesh Kharbanda
- Oxford Heart Centre, The John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK
| | - Sandrine Lecour
- Department of Medicine, Hatter Institute for Cardiovascular Research in Africa and South African Medical Research Council Inter-University Cape Heart Group, Faculty of Health Sciences, University of Cape Town, Chris Barnard Building, Anzio Road, Observatory, Cape Town, Western Cape, 7925, South Africa
| | - Michael Marber
- King's College London BHF Centre, The Rayne Institute, St. Thomas' Hospital, London, UK
| | - Tetsuji Miura
- Department of Cardiovascular, Renal, and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Michel Ovize
- Explorations Fonctionnelles Cardiovasculaires, Hôpital Louis Pradel, Lyon, France.,UMR 1060 (CarMeN), Université Claude Bernard, Lyon 1, France
| | - Miguel A Perez-Pinzon
- Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.,Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.,Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Hans Michael Piper
- Carl von Ossietzky Universität Oldenburg, Ökologiezentrum, Raum 2-116, Uhlhornsweg 99 b, 26129, Oldenburg, Germany
| | - Karin Przyklenk
- Department of Physiology and Emergency Medicine, Cardiovascular Research Institute, Wayne State University, Detroit, MI, USA
| | - Michael Rahbek Schmidt
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, 8 College Road, Singapore, 169857, Singapore
| | - Andrew Redington
- Division of Cardiology, Department of Pediatrics, Heart Institute, Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Marisol Ruiz-Meana
- Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma, Barcelona, Spain
| | - Gemma Vilahur
- Cardiovascular Research Center, CSIC-ICCC, IIB-Hospital Sant Pau, c/Sant Antoni Maria Claret 167, 08025, Barcelona, Spain
| | - Jakob Vinten-Johansen
- Division of Cardiothoracic Surgery, Department of Surgery, Emory University, Atlanta, USA
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, London, UK.,The National Institute of Health Research University College London Hospitals Biomedical Research Centre, London, UK
| | - David Garcia-Dorado
- Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma, Barcelona, Spain.
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Adenosine Receptor Activation in the "Trigger" Limb of Remote Pre-Conditioning Mediates Human Endothelial Conditioning and Release of Circulating Cardioprotective Factor(s). JACC Basic Transl Sci 2016; 1:461-471. [PMID: 30167533 PMCID: PMC6113421 DOI: 10.1016/j.jacbts.2016.06.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 06/09/2016] [Accepted: 06/16/2016] [Indexed: 01/22/2023]
Abstract
Pre-conditioning has emerged as a potentially powerful means of reducing ischemia-reperfusion injury. Several animal models have implicated adenosine in pre-conditioning pathways, but its role in human physiology is unknown. In human volunteers, the authors demonstrate that adenosine receptor activation in “trigger” tissue is an important step in initiating a pre-conditioning signal, but adenosine receptor blockade in “target” tissue does not block the protection afforded by pre-conditioning. The authors also demonstrate that pre-conditioning elaborates a transferrable cardioprotective factor(s) into the serum. This elaboration is prevented by adenosine receptor blockade but can be mirrored by the infusion of exogenous adenosine. An improved understanding of the physiological effectors of pre-conditioning may allow for better targeted clinical studies of pre-conditioning and pre-conditioning mimetics in the future. Remote ischemic pre-conditioning (rIPC) has emerged as a potential mechanism to reduce ischemia-reperfusion injury. Clinical data, however, have been mixed, and its physiological basis remains unclear, although it appears to involve release of circulating factor(s) and/or neural pathways. Here, the authors demonstrate that adenosine receptor activation is an important step in initiating human pre-conditioning; that pre-conditioning liberates circulating cardioprotective factor(s); and that exogenous adenosine infusion is able to recapitulate release of this factor. However, blockade of adenosine receptors in ischemic tissue does not block the protection afforded by pre-conditioning. These data have important implications for defining the physiology of human pre-conditioning and its translation to future clinical trials.
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Zhang Y, Zhang X, Chi D, Wang S, Wei H, Yu H, Li Q, Liu B. Remote Ischemic Preconditioning for Prevention of Acute Kidney Injury in Patients Undergoing On-Pump Cardiac Surgery: A Systematic Review and Meta-Analysis. Medicine (Baltimore) 2016; 95:e3465. [PMID: 27631199 PMCID: PMC5402542 DOI: 10.1097/md.0000000000003465] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Remote ischemic preconditioning (RIPC) may attenuate acute kidney injury (AKI). However, results of studies evaluating the effect of RIPC on AKI after cardiac surgery have been controversial and contradictory.The aim of this meta-analysis is to examine the association between RIPC and AKI after on-pump cardiac surgery.The authors searched relevant studies in PubMed, EMBASE, and the Cochrane Library through December 2015.We considered for inclusion all randomized controlled trials that the role of RIPC in reducing AKI and renal replacement therapy (RRT) among patients underwent on-pump cardiac surgical procedures.We collected the data on AKI, initiation of RRT, serum creatinine (sCr) levels, and in-hospital mortality. Random- and fixed-effect models were used for pooling data.Nineteen trials including 5100 patients were included. The results of this meta-analysis showed a significant benefit of RIPC for reducing the incidence of AKI after cardiac interventions (odds ratio [OR] = 0.84; 95% confidence interval [CI], 0.73-0.98; P = 0.02). No significant difference was found in the incidence of RRT between RIPC and control (OR, 0.76, 95% CI, 0.46-1.24; P = 0.36). In addition, compared with standard medical care, RIPC showed no significant difference in postoperative sCr (IV 0.07; 95% CI, -0.03 to 0.16; P = 0.20; postoperative day 1; IV 0.00; 95% CI, -0.08 to 0.09; P = 0.92; postoperative day 2; IV 0.04; 95% CI, -0.05 to 0.12; P = 0.39; postoperative day 3), and in-hospital mortality (OR, 1.21, 95% CI, 0.64-2.30; P = 0.56).According to the results from present meta-analysis, RIPC was associated with a significant reduction AKI after on-pump cardiac surgery but incidence of RRT, postoperative sCr, and in-hospital mortality. Further high-quality randomized controlled trials and experimental researches comparing RIPC are desirable.
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Affiliation(s)
- Yabing Zhang
- From the Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan (YZ, XZ, DC, SW, HY, QL, BL), and Department of Anesthesiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou (HW), China
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Abstract
OBJECTIVE In this study, we will review the most recently proposed mechanisms for remote ischemic preconditioning and summarize the past 10 years of clinical studies, as well as potential reasons for why, despite over 20 years of research on remote ischemic preconditioning, it is not routinely used in the pediatric critical care patient. In addition, future directions for remote ischemic preconditioning research will be discussed. DATA SOURCES We searched the PubMed database for relevant literature. STUDY SELECTION AND DATA EXTRACTION In PubMed, the search terms "ischemic preconditioning" and "remote preconditioning" were used. Randomized controlled trials published from 2006 until the present time that used a blood pressure cuff to induce remote ischemic preconditioning were included. We also reviewed the reference lists of the articles found in the PubMed search and included those thought to contribute to the objectives. All studies pertaining to remote ischemic preconditioning that included pediatric patients were reviewed. DATA SYNTHESIS AND CONCLUSIONS Differences in study outcomes in the effect of remote ischemic preconditioning on organ protection have been reported and may have played a large role in limiting the translation of findings into routine clinical practice. Ongoing efforts to protocolize the remote ischemic preconditioning technique in large multicenter trials with clearly delineated patient risk groups, including the use of biomarkers for enrichment, may help to ultimately determine if this procedure can be safely and effectively used for critically ill children.
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Abstract
OBJECTIVE Acute kidney injury is a common complication in critically ill patients and is associated with increased morbidity and mortality. Sepsis, major surgery, and nephrotoxic drugs are the most common causes of acute kidney injury. There is currently no effective strategy available to prevent or treat acute kidney injury. Therefore, novel treatment regimens are required to decrease acute kidney injury prevalence and to improve clinical outcomes. Remote ischemic preconditioning, triggered by brief episodes of ischemia and reperfusion applied in distant tissues or organs before the injury of the target organ, attempts to invoke adaptive responses that protect against acute kidney injury. We sought to evaluate the clinical evidence for remote ischemic preconditioning as a potential strategy to protect the kidney and to review the underlying mechanisms in light of recent studies. DATA SOURCES We searched PubMed for studies reporting the effect of remote ischemic preconditioning on kidney function in surgical patients (search terms: "remote ischemic preconditioning," "kidney function," and "surgery"). We also reviewed bibliographies of relevant articles to identify additional citations. STUDY SELECTION Published studies, consisting of randomized controlled trials, are reviewed. DATA EXTRACTION The authors used consensus to summarize the evidence behind the use of remote ischemic preconditioning. DATA SYNTHESIS In addition, the authors suggest patient populations and clinical scenarios in which remote ischemic preconditioning might be best applied. CONCLUSIONS Several experimental and clinical studies have shown tissue-protective effects of remote ischemic preconditioning in various target organs, including the kidneys. Remote ischemic preconditioning may offer a novel, noninvasive, and inexpensive treatment strategy for decreasing acute kidney injury prevalence in high-risk patients. Although many new studies have further advanced our knowledge in this area, the appropriate intensity of remote ischemic preconditioning, its mechanisms of action, and the role of biomarkers for patient selection and monitoring are still unknown.
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Karami A, Khosravi MB, Shafa M, Azemati S, Khademi S, Akhlagh SH, Maghsodi B. Cardioprotective Effect of Extended Remote Ischemic Preconditioning in Patients Coronary Artery Bypass Grafting Undergoing: A Randomized Clinical Trial. IRANIAN JOURNAL OF MEDICAL SCIENCES 2016; 41:265-74. [PMID: 27365547 PMCID: PMC4912644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
BACKGROUND The cardioprotective effect of ischemic preconditioning has been known for many years. Since the temporary ischemia in the heart may cause lethal cardiac effects, the idea of creating ischemia in organs far from the heart such as limbs was raised as remote ischemic preconditioning (RIPC). We hypothesized that the extension of RIPC has more cardioprotective effect in patients undergoing coronary artery bypass graft (CABG) surgeries. METHODS In this triple-blind randomized clinical trial study, 96 patients were randomly divided into 3 groups and two blood pressure cuffs were placed on both upper and lower extremities. In group A, only upper extremity cuff and in group B upper limb and lower limb cuff was inflated intermittently and group C was the control group. RIPC was induced with three 5-min cycles of cuff inflation about 100 mmHg over the initial systolic blood pressure before starting cardiopulmonary bypass. The primary endpoints were troponin I and creatine phosphokinase-myoglobin isoenzyme (CK-MB). RESULTS Six hours after the termination of CPB, there was a peak release of the troponin I level in all groups (group A=4.90 ng/ml, group B=4.40 ng/ml, and group C=4.50 ng/ml). There was a rise in plasma CK-MB in all groups postoperatively and there were not any significant differences in troponin I and CK-MB release between the three groups. CONCLUSION RIPC induced by upper and lower limb ischemia does not reduce postoperative myocardial enzyme elevation in adult patients undergoing CABG. TRIAL REGISTRATION NUMBER IRCT2012071710311N1.
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Affiliation(s)
- Ali Karami
- Shiraz Anesthesiology and Critical Care Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohamad Bagher Khosravi
- Shiraz Anesthesiology and Critical Care Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran,Correspondence: Mohamad Bagher Khosravi, MD; Department of Anesthesiology, Faghihi Hospital, Karimkhan-e Zand Avenue, Shiraz, Iran Post Code: 71348-44119, Tel: +98 71 32318072 Fax: +98 71 32307072
| | - Masih Shafa
- Department of Cardiac Surgery, Faghihi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Simin Azemati
- Shiraz Anesthesiology and Critical Care Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeed Khademi
- Shiraz Anesthesiology and Critical Care Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Hedayatalla Akhlagh
- Shiraz Anesthesiology and Critical Care Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Behzad Maghsodi
- Shiraz Anesthesiology and Critical Care Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
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Galagudza MM, Sonin DL, Vlasov TD, Kurapeev DI, Shlyakhto EV. Remote vs. local ischaemic preconditioning in the rat heart: infarct limitation, suppression of ischaemic arrhythmia and the role of reactive oxygen species. Int J Exp Pathol 2016; 97:66-74. [PMID: 26990944 DOI: 10.1111/iep.12170] [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: 06/05/2015] [Accepted: 12/30/2015] [Indexed: 12/13/2022] Open
Abstract
The unmet clinical need for myocardial salvage during ischaemia-reperfusion injury requires the development of new techniques for myocardial protection. In this study the protective effect of different local ischaemic preconditioning (LIPC) and remote ischaemic preconditioning (RIPC) protocols was compared in the rat model of myocardial ischaemia-reperfusion, using infarct size and ischaemic tachyarrhythmias as end-points. In addition, the hypothesis that there is involvement of reactive oxygen species (ROS) in the protective signalling by RIPC was tested, again in comparison with LIPC. The animals were subjected to 30-min coronary occlusion and 90-min reperfusion. RIPC protocol included either transient infrarenal aortic occlusion (for 5, 15 and 30 min followed by 15-min reperfusion) or 15-min mesenteric artery occlusion with 15-min reperfusion. Ventricular tachyarrhythmias during test ischaemia were quantified according to Lambeth Conventions. It was found that the infarct-limiting effect of RIPC critically depends on the duration of a single episode of remote ischaemia, which fails to protect the heart from infarction when it is too short or, instead, too prolonged. It was also shown that RIPC is ineffective in reducing the incidence and severity of ischaemia-induced ventricular tachyarrhythmias. According to our data, the infarct-limiting effect of LIPC could be partially eliminated by the administration of ROS scavenger N-2-mercaptopropionylglycine (90 mg/kg), whereas the same effect of RIPC seems to be independent of ROS signalling.
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Affiliation(s)
- Michael M Galagudza
- Institute of Experimental Medicine, Federal Almazov North-West Medical Research Centre, St. Petersburg, Russian Federation.,ITMO University, St. Petersburg, Russian Federation
| | - Dmitry L Sonin
- Institute of Experimental Medicine, Federal Almazov North-West Medical Research Centre, St. Petersburg, Russian Federation.,Department of Pathophysiology, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Timur D Vlasov
- Institute of Experimental Medicine, Federal Almazov North-West Medical Research Centre, St. Petersburg, Russian Federation.,Department of Pathophysiology, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Dmitry I Kurapeev
- Institute of Experimental Medicine, Federal Almazov North-West Medical Research Centre, St. Petersburg, Russian Federation
| | - Eugene V Shlyakhto
- Institute of Heart and Vessels, Federal Almazov North-West Medical Research Centre, St. Petersburg, Russian Federation.,Department of Internal Medicine, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
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Remote ischemic conditioning for kidney protection: A meta-analysis. J Crit Care 2016; 33:224-32. [PMID: 26936039 DOI: 10.1016/j.jcrc.2016.01.026] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 12/30/2015] [Accepted: 01/31/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Results from randomized controlled trials (RCTs) concerning kidney effect of remote ischemic conditioning (RIC) are inconsistent. METHODS We searched for relevant studies in Medline, Embase, the Cochrane Library, Google Scholar and Chinese database (SinoMed), as well as relevant references from their inception to November 2015. We performed a systematic review and meta-analysis of all eligible RCTs of RIC with kidney events. RESULTS We included 37 RCTs from 2007 to 2015 involving 8168 patients. Pooled analyses of all RCTs showed RIC significantly reduced the incidence of investigator-defined acute kidney injury (AKI) compared with control groups (RR 0.84, 95% CI 0.73-0.96, P = .009) (I(2) = 25%). However, the difference was not significant when only RIFLE (Risk, Injury, Failure, Loss, End Stage), AKIN (Acute Kidney Injury Network), or KDIGO (Kidney Disease Improving Global Outcomes) criteria were applied to the definition of AKI (RR 0.87, 95% CI 0.74-1.02, P = .08) (I(2) = 22%). In subgroup analysis, RIC showed a significant benefit on reducing investigator-defined AKI in patients following percutaneous coronary intervention (RR 0.64, 95% CI 0.46-0.87), but not after cardiac surgery (RR 0.93, 95% CI 0.82-1.06). There was no difference for changes in the incidence of renal replacement therapy, estimated glomerular filtration rate or serum creatinine. CONCLUSIONS RIC might be beneficial for the prevention of investigator-defined AKI; however, the effect is likely small. Moreover, due to lack of an effect on use of renal replacement therapy, estimated glomerular filtration rate, RIFLE, AKIN, or KDIGO-defined AKI, and serum creatinine, the evidence for RIC is not robust. Finally, recent large-scale RCTs of RIC focusing on patient-centered outcomes do not support the wider application of RIC.
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49
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Remote ischemic preconditioning in aortic valve surgery: Results of a randomized controlled study. J Cardiol 2016; 67:36-41. [DOI: 10.1016/j.jjcc.2015.06.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 05/13/2015] [Accepted: 06/01/2015] [Indexed: 02/06/2023]
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50
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Walsh M, Whitlock R, Garg AX, Légaré JF, Duncan AE, Zimmerman R, Miller S, Fremes S, Kieser T, Karthikeyan G, Chan M, Ho A, Nasr V, Vincent J, Ali I, Lavi R, Sessler DI, Kramer R, Gardner J, Syed S, VanHelder T, Guyatt G, Rao-Melacini P, Thabane L, Devereaux PJ. Effects of remote ischemic preconditioning in high-risk patients undergoing cardiac surgery (Remote IMPACT): a randomized controlled trial. CMAJ 2015; 188:329-336. [PMID: 26668200 DOI: 10.1503/cmaj.150632] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2015] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Remote ischemic preconditioning is a simple therapy that may reduce cardiac and kidney injury. We undertook a randomized controlled trial to evaluate the effect of this therapy on markers of heart and kidney injury after cardiac surgery. METHODS Patients at high risk of death within 30 days after cardiac surgery were randomly assigned to undergo remote ischemic preconditioning or a sham procedure after induction of anesthesia. The preconditioning therapy was three 5-minute cycles of thigh ischemia, with 5 minutes of reperfusion between cycles. The sham procedure was identical except that ischemia was not induced. The primary outcome was peak creatine kinase-myocardial band (CK-MB) within 24 hours after surgery (expressed as multiples of the upper limit of normal, with log transformation). The secondary outcome was change in creatinine level within 4 days after surgery (expressed as log-transformed micromoles per litre). Patient-important outcomes were assessed up to 6 months after randomization. RESULTS We randomly assigned 128 patients to remote ischemic preconditioning and 130 to the sham therapy. There were no significant differences in postoperative CK-MB (absolute mean difference 0.15, 95% confidence interval [CI] -0.07 to 0.36) or creatinine (absolute mean difference 0.06, 95% CI -0.10 to 0.23). Other outcomes did not differ significantly for remote ischemic preconditioning relative to the sham therapy: for myocardial infarction, relative risk (RR) 1.35 (95% CI 0.85 to 2.17); for acute kidney injury, RR 1.10 (95% CI 0.68 to 1.78); for stroke, RR 1.02 (95% CI 0.34 to 3.07); and for death, RR 1.47 (95% CI 0.65 to 3.31). INTERPRETATION Remote ischemic precnditioning did not reduce myocardial or kidney injury during cardiac surgery. This type of therapy is unlikely to substantially improve patient-important outcomes in cardiac surgery. TRIAL REGISTRATION ClinicalTrials.gov, no. NCT01071265.
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Affiliation(s)
- Michael Walsh
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Richard Whitlock
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Amit X Garg
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Jean-François Légaré
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Andra E Duncan
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Robert Zimmerman
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Scott Miller
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Stephen Fremes
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Teresa Kieser
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Ganesan Karthikeyan
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Matthew Chan
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Anthony Ho
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Vivian Nasr
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Jessica Vincent
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Imtiaz Ali
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Ronit Lavi
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Daniel I Sessler
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Robert Kramer
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Jeff Gardner
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Summer Syed
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Tomas VanHelder
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Gordon Guyatt
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Purnima Rao-Melacini
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - Lehana Thabane
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
| | - P J Devereaux
- Population Health Research Institute (Walsh, Whitlock, Vincent, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; McMaster University (Walsh, Whitlock, Syed, VanHelder, Guyatt, Rao-Melacini, Thabane, Devereaux), Hamilton, Ont.; London Health Sciences Centre (Garg, Lavi), Western University, London, Ont.; Dalhousie University (Légaré), Halifax, NS; Cleveland Clinic (Duncan, Nasr, Sessler), Cleveland, Ohio; Maine Medical Center (Zimmerman, Kramer), Portland, Me.; Wake Forest University (Miller, Gardner), Winston-Salem, NC; Sunnybrook Health Sciences Centre (Fremes), University of Toronto, Toronto, Ont.; University of Calgary (Kieser, Ali), Calgary, Alta.; All India Institute of Medical Sciences (Karthikeyan), New Delhi, India; The Chinese University of Hong Kong (Chan, Ho), Hong Kong SAR, China
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