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Karimi E, Gholizadeh M, Abdolahi M, Sedighiyan M, Salehinia F, Siri G, Asanjarani B, Yousefi A, Gandomkar H, Abdollahi H. Effect of vitamin B1 supplementation on blood creatinine and lactate levels and clinical outcomes in patients in intensive care units: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev 2024; 82:804-814. [PMID: 37553224 DOI: 10.1093/nutrit/nuad096] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023] Open
Abstract
CONTEXT The metabolic response to stress can deplete the remaining thiamine stores, leading to thiamine deficiency. OBJECTIVE This study is the first meta-analysis of the effectiveness of thiamine supplementation on clinical and biochemical outcomes in adult patients admitted to the intensive care unit (ICU). DATA SOURCES Scopus, PubMed, and Cochrane databases were searched to select studies up to 20 November 2022. STUDY SELECTION Studies investigating the effect of thiamine supplementation on serum lactate and creatinine levels, the need for renal replacement therapy, length of ICU stay, and mortality rate in ICU patients were selected. DATA EXTRACTION After excluding studies based on title and abstract screening, 2 independent investigators reviewed the full texts of the remaining articles. In the next step, a third investigator resolved any discrepancy in the article selection process. RESULTS Of 1628 retrieved articles, 8 were selected for final analysis. This study showed that thiamine supplementation reduced the serum creatinine level (P = .03) compared with placebo. In addition, according to subgroup analysis, serum creatinine concentration was significantly lower in patients >60 years old (P < .00001). However, there was no statistically significant difference in the lactate level between the thiamine supplementation and placebo groups (P = .26). Thiamine supplementation did not decrease the risk of all-cause mortality (P = .71) or the need for renal replacement therapy (P = .14). The pooled results of eligible randomized controlled trials also showed that thiamine supplementation did not reduce the length of ICU stay in comparison to the placebo group (P = .39). CONCLUSION This meta-analysis provides evidence that thiamine supplementation has a protective effect against blood creatinine increase in ICU patients. However, further high-quality trials are needed to discover the effect of thiamine supplementation on clinical and biochemical outcomes in ICU patients. SYSTEMATIC REVIEW REGISTRATION PROSPERO no. CRD42023399710 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=399710).
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Affiliation(s)
- Elmira Karimi
- Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria, Australia
| | - Mohammad Gholizadeh
- Faculty of Nutrition and Food Technology, Department of Clinical Nutrition, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mina Abdolahi
- Department of Clinical Nutrition, Amir Alam Hospital Complexes, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Sedighiyan
- Faculty of Nutrition and Food Technology, Department of Clinical Nutrition, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farahnaz Salehinia
- Department of Internal Medicine, Amir Alam Hospital Complexes, Tehran University of Medical Sciences, Tehran, Iran
| | - Goli Siri
- Department of Internal Medicine, Amir Alam Hospital Complexes, Tehran University of Medical Sciences, Tehran, Iran
| | - Behzad Asanjarani
- Department of Internal Medicine, Amir Alam Hospital Complexes, Tehran University of Medical Sciences, Tehran, Iran
| | - Abolghasem Yousefi
- Department of Anesthesiology, Amir Alam Hospital Complexes, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Gandomkar
- Amir Alam Hospital Complexes, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Abdollahi
- Department of Anesthesiology, Amir Alam Hospital Complexes, Tehran University of Medical Sciences, Tehran, Iran
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Vine J, Lee JH, Kravitz MS, Grossestreuer AV, Balaji L, Leland SB, Berlin N, Moskowitz A, Donnino MW. Thiamine administration in septic shock: a post hoc analysis of two randomized trials. Crit Care 2024; 28:41. [PMID: 38321529 PMCID: PMC10845751 DOI: 10.1186/s13054-024-04818-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/25/2024] [Indexed: 02/08/2024] Open
Abstract
BACKGROUND This is a post hoc analysis of combined cohorts from two previous Phase II clinical trials to assess the effect of thiamine administration on kidney protection and mortality in patients with septic shock. METHODS Patient-level data from the Thiamine in Septic Shock Trial (NCT01070810) and the Thiamine for Renal Protection in Septic Shock Trial (NCT03550794) were combined in this analysis. The primary outcome for the current study was survival without the receipt of renal replacement therapy (RRT). Analyses were performed on the overall cohort and the thiamine-deficient cohort (thiamine < 8 nmol/L). RESULTS Totally, 158 patients were included. Overall, thiamine administration was associated with higher odds of being alive and RRT-free (adjusted odds ratio [aOR]: 2.05 [95% confidence interval (CI) 1.08-3.90]) and not needing RRT (aOR: 2.59 [95% CI 1.01-6.62]). In the thiamine-deficient group, thiamine administration was associated with higher odds of being alive and RRT-free (aOR: 8.17 [95% CI 1.79-37.22]) and surviving to hospital discharge (aOR: 6.84 [95% CI 1.54-30.36]). There was a significant effect modification by baseline thiamine deficiency for alive and RRT-free (interaction, p = 0.016) and surviving to hospital discharge (p = 0.019). CONCLUSION In the combined analysis of two previous randomized trials, thiamine administration was associated with higher odds of being alive and RRT-free at hospital discharge in patients with septic shock. This signal was stronger in patients with thiamine deficiency.
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Affiliation(s)
- Jacob Vine
- Center for Resuscitation Science, Beth Israel Deaconess Medical Center, Boston, MA, USA.
| | - John H Lee
- Center for Resuscitation Science, Beth Israel Deaconess Medical Center, Boston, MA, USA.
- Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
| | - Max S Kravitz
- Center for Resuscitation Science, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Anne V Grossestreuer
- Center for Resuscitation Science, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Lakshman Balaji
- Center for Resuscitation Science, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Shannon B Leland
- Center for Resuscitation Science, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Noa Berlin
- Center for Resuscitation Science, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA, USA
| | - Ari Moskowitz
- Center for Resuscitation Science, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Critical Care Medicine, Montefiore Medical Center, The Bronx, NY, USA
- Bronx Center for Critical Care Outcomes and Resuscitation Research, The Bronx, NY, USA
| | - Michael W Donnino
- Center for Resuscitation Science, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Bosco M, Romero R, Gallo DM, Suksai M, Gotsch F, Jung E, Chaemsaithong P, Tarca AL, Gomez-Lopez N, Arenas-Hernandez M, Meyyazhagan A, Al Qasem M, Franchi MP, Grossman LI, Aras S, Chaiworapongsa T. Clinical chorioamnionitis at term is characterized by changes in the plasma concentration of CHCHD2/MNRR1, a mitochondrial protein. J Matern Fetal Neonatal Med 2023; 36:2222333. [PMID: 37349086 PMCID: PMC10445405 DOI: 10.1080/14767058.2023.2222333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 06/02/2023] [Accepted: 06/02/2023] [Indexed: 06/24/2023]
Abstract
OBJECTIVE Mitochondrial dysfunction was observed in acute systemic inflammatory conditions such as sepsis and might be involved in sepsis-induced multi-organ failure. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2), also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1), a bi-organellar protein located in the mitochondria and the nucleus, is implicated in cell respiration, survival, and response to tissue hypoxia. Recently, the reduction of the cellular CHCHD2/MNRR1 protein, as part of mitochondrial dysfunction, has been shown to play a role in the amplification of inflammatory cytokines in a murine model of lipopolysaccharide-induced systemic inflammation. The aim of this study was to determine whether the plasma concentration of CHCHD2/MNRR1 changed during human normal pregnancy, spontaneous labor at term, and clinical chorioamnionitis at term. METHODS We conducted a cross-sectional study that included the following groups: 1) non-pregnant women (n = 17); 2) normal pregnant women at various gestational ages from the first trimester until term (n = 110); 3) women at term with spontaneous labor (n = 50); and 4) women with clinical chorioamnionitis at term in labor (n = 25). Plasma concentrations of CHCHD2/MNRR1 were assessed by an enzyme-linked immunosorbent assay. RESULTS 1) Pregnant women at term in labor with clinical chorioamnionitis had a significantly higher plasma CHCHD2/MNRR1 concentration than those in labor without chorioamnionitis (p = .003); 2) CHCHD2/MNRR1 is present in the plasma of healthy non-pregnant and normal pregnant women without significant differences in its plasma concentrations between the two groups; 3) there was no correlation between maternal plasma CHCHD2/MNRR1 concentration and gestational age at venipuncture; and 4) plasma CHCHD2/MNRR1 concentration was not significantly different in women at term in spontaneous labor compared to those not in labor. CONCLUSIONS CHCHD2/MNRR1 is physiologically present in the plasma of healthy non-pregnant and normal pregnant women, and its concentration does not change with gestational age and parturition at term. However, plasma CHCHD2/MNRR1 is elevated in women at term with clinical chorioamnionitis. CHCHD2/MNRR1, a novel bi-organellar protein located in the mitochondria and the nucleus, is released into maternal plasma during systemic inflammation.
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Affiliation(s)
- Mariachiara Bosco
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, Verona, Italy
| | - Roberto Romero
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA
- Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA
| | - Dahiana M Gallo
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Gynecology and Obstetrics, Universidad del Valle, Cali, Colombia
| | - Manaphat Suksai
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Obstetrics and Gynecology, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Francesca Gotsch
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Eunjung Jung
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Obstetrics and Gynecology, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Piya Chaemsaithong
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Obstetrics and Gynecology, Mahidol University, Bangkok, Thailand
| | - Adi L Tarca
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Computer Science, Wayne State University College of Engineering, Detroit, MI, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
| | - Nardhy Gomez-Lopez
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
- Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Marcia Arenas-Hernandez
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Arun Meyyazhagan
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Centre of Perinatal and Reproductive Medicine, University of Perugia, Perugia, Italy
| | - Malek Al Qasem
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Obstetrics and Gynecology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Massimo P Franchi
- Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, Verona, Italy
| | - Lawrence I Grossman
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
| | - Siddhesh Aras
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
| | - Tinnakorn Chaiworapongsa
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
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Bosco M, Romero R, Gallo DM, Suksai M, Gotsch F, Jung E, Chaemsaithong P, Tarca AL, Gomez-Lopez N, Arenas-Hernandez M, Meyyazhagan A, Al Qasem M, Franchi MP, Grossman LI, Aras S, Chaiworapongsa T. Evidence for the participation of CHCHD2/MNRR1, a mitochondrial protein, in spontaneous labor at term and in preterm labor with intra-amniotic infection. J Matern Fetal Neonatal Med 2023; 36:2183088. [PMID: 36941246 PMCID: PMC10352953 DOI: 10.1080/14767058.2023.2183088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 02/15/2023] [Indexed: 03/23/2023]
Abstract
OBJECTIVE Intra-amniotic inflammation (IAI), associated with either microbe (infection) or danger signals (sterile), plays a major role in the pathophysiology of preterm labor and delivery. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2) [also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1)], a mitochondrial protein involved in oxidative phosphorylation and cell survival, is capable of sensing tissue hypoxia and inflammatory signaling. The ability to maintain an appropriate energy balance at the cellular level while adapting to environmental stress is essential for the survival of an organism. Mitochondrial dysfunction has been observed in acute systemic inflammatory conditions, such as sepsis, and is proposed to be involved in sepsis-induced multi-organ failure. The purpose of this study was to determine the amniotic fluid concentrations of CHCHD2/MNRR1 in pregnant women, women at term in labor, and those in preterm labor (PTL) with and without IAI. METHODS This cross-sectional study comprised patients allocated to the following groups: (1) mid-trimester (n = 16); (2) term in labor (n = 37); (3) term not in labor (n = 22); (4) PTL without IAI who delivered at term (n = 25); (5) PTL without IAI who delivered preterm (n = 47); and (6) PTL with IAI who delivered preterm (n = 53). Diagnosis of IAI (amniotic fluid interleukin-6 concentration ≥2.6 ng/mL) included cases associated with microbial invasion of the amniotic cavity and those of sterile nature (absence of detectable bacteria, using culture and molecular microbiology techniques). Amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations were determined with a validated and sensitive immunoassay. RESULTS (1) CHCHD2/MNRR1 was detectable in all amniotic fluid samples and women at term without labor had a higher amniotic fluid CHCHD2/MNRR1 concentration than those in the mid-trimester (p = 0.003); (2) the amniotic fluid concentration of CHCHD2/MNRR1 in women at term in labor was higher than that in women at term without labor (p = 0.01); (3) women with PTL and IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those without IAI, either with preterm (p < 0.001) or term delivery (p = 0.01); (4) women with microbial-associated IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those with sterile IAI (p < 0.001); (5) among women with PTL and IAI, the amniotic fluid concentration of CHCHD2/MNRR1 correlated with that of interleukin-6 (Spearman's Rho = 0.7; p < 0.001); and (6) no correlation was observed between amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations among women with PTL. CONCLUSION CHCHD2/MNRR1 is a physiological constituent of human amniotic fluid in normal pregnancy, and the amniotic concentration of this mitochondrial protein increases during pregnancy, labor at term, and preterm labor with intra-amniotic infection. Hence, CHCHD2/MNRR1 may be released into the amniotic cavity by dysfunctional mitochondria during microbial-associated IAI.
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Affiliation(s)
- Mariachiara Bosco
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, Verona, Italy
| | - Roberto Romero
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA
- Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
- Detroit Medical Center, Detroit, MI, USA
| | - Dahiana M. Gallo
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Gynecology and Obstetrics, Universidad del Valle, Cali, Colombia
| | - Manaphat Suksai
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Francesca Gotsch
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Eunjung Jung
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Piya Chaemsaithong
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Obstetrics and Gynecology, Mahidol University, Bangkok, Thailand
| | - Adi L. Tarca
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Computer Science, Wayne State University College of Engineering, Detroit, MI, USA
| | - Nardhy Gomez-Lopez
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Marcia Arenas-Hernandez
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Arun Meyyazhagan
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Centre of Perinatal and Reproductive Medicine, University of Perugia, Perugia, Italy
| | - Malek Al Qasem
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
- Department of Obstetrics and Gynecology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
| | - Massimo P. Franchi
- Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, Verona, Italy
| | - Lawrence I. Grossman
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
| | - Siddhesh Aras
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
| | - Tinnakorn Chaiworapongsa
- Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
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Harrington JS, Ryter SW, Plataki M, Price DR, Choi AMK. Mitochondria in health, disease, and aging. Physiol Rev 2023; 103:2349-2422. [PMID: 37021870 PMCID: PMC10393386 DOI: 10.1152/physrev.00058.2021] [Citation(s) in RCA: 250] [Impact Index Per Article: 125.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/07/2023] Open
Abstract
Mitochondria are well known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. Although oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.
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Affiliation(s)
- John S Harrington
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medicine, New York, New York, United States
| | | | - Maria Plataki
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medicine, New York, New York, United States
| | - David R Price
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medicine, New York, New York, United States
| | - Augustine M K Choi
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medicine, New York, New York, United States
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6
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Moskowitz A, Berg KM, Grossestreuer AV, Balaji L, Liu X, Cocchi MN, Chase M, Gong MN, Gong J, Parikh SM, Ngo L, Berlin N, Donnino MW. Thiamine for Renal Protection in Septic Shock (TRPSS): A Randomized, Placebo-controlled, Clinical Trial. Am J Respir Crit Care Med 2023; 208:570-578. [PMID: 37364280 PMCID: PMC10492240 DOI: 10.1164/rccm.202301-0034oc] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 06/20/2023] [Indexed: 06/28/2023] Open
Abstract
Rationale: Kidney injury is common and associated with worse outcomes in patients with septic shock. Mitochondrial resuscitation with thiamine (vitamin B1) may attenuate septic kidney injury. Objectives: To assess whether thiamine supplementation attenuates kidney injury in septic shock. Methods: The TRPSS (Thiamine for Renal Protection in Septic Shock) trial was a multicenter, randomized, placebo-controlled trial of thiamine versus placebo in septic shock. The primary outcome was change in serum creatinine between enrollment and 72 hours after enrollment. Measurements and Main Results: Eighty-eight patients were enrolled (42 patients received the intervention, and 46 received placebo). There was no significant between-groups difference in creatinine at 72 hours (mean difference, -0.57 mg/dl; 95% confidence interval, -1.18, 0.04; P = 0.07). There was no difference in receipt of kidney replacement therapy (14.3% vs. 21.7%, P = 0.34), acute kidney injury (as defined by stage 3 of the Kidney Disease: Improving Global Outcomes acute kidney injury scale; 54.7% vs. 73.9%, P = 0.07), or mortality (35.7% vs. 54.3%, P = 0.14) between the thiamine and placebo groups. Patients who received thiamine had more ICU-free days (median [interquartile range]: 22.5 [0.0-25.0] vs. 0.0 [0.0-23.0], P < 0.01). In the thiamine-deficient cohort (27.4% of patients), there was no difference in rates of kidney failure (57.1% thiamine vs. 81.5% placebo) or in-hospital mortality (28.6% vs. 68.8%) between groups. Conclusions: In the TRPSS trial, there was no statistically significant difference in the primary outcome of change in creatinine over time. Patients who received thiamine had more ICU-free days, but there was no difference in other secondary outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT03550794).
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Affiliation(s)
- Ari Moskowitz
- Division of Critical Care Medicine, Montefiore Medical Center, The Bronx, New York
- Bronx Center for Critical Care Outcomes and Resuscitation Research, The Bronx, New York
- Center for Resuscitation Science
| | - Katherine M. Berg
- Center for Resuscitation Science
- Division of Pulmonary, Critical Care, and Sleep Medicine
| | | | - Lakshman Balaji
- Center for Resuscitation Science
- Department of Emergency Medicine, and
| | | | - Michael N. Cocchi
- Center for Resuscitation Science
- Department of Emergency Medicine, and
| | - Maureen Chase
- Center for Resuscitation Science
- Department of Emergency Medicine, and
| | - Michelle Ng Gong
- Division of Critical Care Medicine, Montefiore Medical Center, The Bronx, New York
- Bronx Center for Critical Care Outcomes and Resuscitation Research, The Bronx, New York
| | - Jonathan Gong
- Department of Emergency Medicine, Long Island Jewish Medical Center, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York; and
| | - Samir M. Parikh
- Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Long Ngo
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | | | - Michael W. Donnino
- Center for Resuscitation Science
- Division of Pulmonary, Critical Care, and Sleep Medicine
- Department of Emergency Medicine, and
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7
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Taiana M, Tomasella I, Russo A, Lerose A, Ceola Graziadei M, Corubolo L, Rama J, Schweiger V, Vignola A, Polati E, Luciani GB, Onorati F, Donadello K, Gottin L. Analysis of P(v-a)CO 2/C(a-v)O 2 Ratio and Other Perfusion Markers in a Population of 98 Pediatric Patients Undergoing Cardiac Surgery. J Clin Med 2023; 12:5700. [PMID: 37685767 PMCID: PMC10488867 DOI: 10.3390/jcm12175700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 08/23/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
BACKGROUND The so-called Low Cardiac Output Syndrome (LCOS) is one of the most common complications in pediatric patients with congenital heart disease undergoing corrective surgery. LCOS requires high concentrations of inotropes to support cardiac contractility and improve cardiac output, allowing for better systemic perfusion. To date, serum lactate concentrations and central venous oxygen saturation (ScVO2) are the most commonly used perfusion markers, but they are not completely reliable in identifying a state of global tissue hypoxia. The study aims to evaluate whether the venoarterial carbon dioxide difference/arterial-venous oxygen difference ratio [P(v-a)CO2/C(a-v)O2] can be a good index to predict the development of LCOS in the aforementioned patients, so as to treat it promptly. METHODS This study followed a population of 98 children undergoing corrective cardiac surgery from June 2018 to October 2020 at the Department of Cardiac Surgery of University Hospital Integrated Trust and their subsequent admission at the Postoperative Cardiothoracic Surgery Intensive Care Unit. During the study, central arterial and venous blood gas analyses were carried out before and after cardiopulmonary bypass (CPB) (pre-CPB and post-CPB), at admission to the intensive care unit, before and after extubation, and at any time of instability or modification of the patient's clinical and therapeutic conditions. RESULTS The data analysis shows that 46.9% of the children developed LCOS (in line with the current literature) but that there is no statistically significant association between the P(v-a)CO2/C(a-v)O2 ratio and LCOS onset. Despite the limits of statistical significance, however, a 31% increase in the ratio emerged from the pre-CPB phase to the post-CPB phase when LCOS is present. CONCLUSIONS This study confirms a statistically significant association between the most used markers in adult patients (serum lactate concentration, ScVO2, and oxygen extraction ratio-ERO2) measured in the pre-CPB phase and the incidence of LCOS onset, especially in patients with hemodynamic instability before surgery.
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Affiliation(s)
- Matteo Taiana
- Cardiothoracic and Vascular Intensive Care Unit, Hospital and University Trust of Verona, P. le A. Stefani, 37124 Verona, Italy; (I.T.); (A.R.); (M.C.G.); (L.C.); (J.R.); (L.G.)
| | - Irene Tomasella
- Cardiothoracic and Vascular Intensive Care Unit, Hospital and University Trust of Verona, P. le A. Stefani, 37124 Verona, Italy; (I.T.); (A.R.); (M.C.G.); (L.C.); (J.R.); (L.G.)
| | - Alessandro Russo
- Cardiothoracic and Vascular Intensive Care Unit, Hospital and University Trust of Verona, P. le A. Stefani, 37124 Verona, Italy; (I.T.); (A.R.); (M.C.G.); (L.C.); (J.R.); (L.G.)
| | - Annalisa Lerose
- Anesthesia and Intensive Care Unit, Magalini Hospital ULSS 9 Scaligera, Villafranca, 37069 Verona, Italy;
| | - Marcello Ceola Graziadei
- Cardiothoracic and Vascular Intensive Care Unit, Hospital and University Trust of Verona, P. le A. Stefani, 37124 Verona, Italy; (I.T.); (A.R.); (M.C.G.); (L.C.); (J.R.); (L.G.)
| | - Luisa Corubolo
- Cardiothoracic and Vascular Intensive Care Unit, Hospital and University Trust of Verona, P. le A. Stefani, 37124 Verona, Italy; (I.T.); (A.R.); (M.C.G.); (L.C.); (J.R.); (L.G.)
| | - Jacopo Rama
- Cardiothoracic and Vascular Intensive Care Unit, Hospital and University Trust of Verona, P. le A. Stefani, 37124 Verona, Italy; (I.T.); (A.R.); (M.C.G.); (L.C.); (J.R.); (L.G.)
| | - Vittorio Schweiger
- Anesthesia and Intensive Care Unit, Policlinico G.B. Rossi, Hospital and University Trust of Verona, P. le L. Scuro, 37129 Verona, Italy; (V.S.); (E.P.); (K.D.)
| | - Alessandro Vignola
- Emergency Medicine Department, Hospital and University Trust of Verona, P. le A. Stefani, 37126 Verona, Italy
| | - Enrico Polati
- Anesthesia and Intensive Care Unit, Policlinico G.B. Rossi, Hospital and University Trust of Verona, P. le L. Scuro, 37129 Verona, Italy; (V.S.); (E.P.); (K.D.)
| | - Giovanni Battista Luciani
- Cardiac Surgery Unit, Hospital and University Trust of Verona, P. le A. Stefani, 37126 Verona, Italy; (G.B.L.); (F.O.)
| | - Francesco Onorati
- Cardiac Surgery Unit, Hospital and University Trust of Verona, P. le A. Stefani, 37126 Verona, Italy; (G.B.L.); (F.O.)
| | - Katia Donadello
- Anesthesia and Intensive Care Unit, Policlinico G.B. Rossi, Hospital and University Trust of Verona, P. le L. Scuro, 37129 Verona, Italy; (V.S.); (E.P.); (K.D.)
| | - Leonardo Gottin
- Cardiothoracic and Vascular Intensive Care Unit, Hospital and University Trust of Verona, P. le A. Stefani, 37124 Verona, Italy; (I.T.); (A.R.); (M.C.G.); (L.C.); (J.R.); (L.G.)
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8
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Mihaljevic O, Zivancevic-Simonovic S, Jovanovic D, Drakulic SM, Vukajlovic JT, Markovic A, Pirkovic MS, Srejovic I, Jakovljevic V, Milosevic-Djordjevic O. Oxidative stress and DNA damage in critically ill patients with sepsis. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2023; 889:503655. [PMID: 37491118 DOI: 10.1016/j.mrgentox.2023.503655] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 06/02/2023] [Accepted: 06/29/2023] [Indexed: 07/27/2023]
Abstract
The aim of our study was to assess the oxidative stress and inflammatory status in critically ill patients with sepsis as well as their relationship with the level of DNA damage. The study also evaluated the influence of all analyzed parameters on the outcome of the patients. The study included 27 critically ill patients with sepsis and 20 healthy subjects. Comet Assay was used for the measurement of the level of DNA damage, expressed as genetic damage index (GDI). Both oxidative stress parameters and the antioxidant parameters were obtained spectrophotometrically. The standard laboratory methods and the appropriate autoanalyzers were performed for determination the parameters of inflammation. A higher level of oxidative stress and more pronounced inflammation were found in the patients with sepsis compared to healthy subjects. The activity of the antioxidant enzymes was statistically declined in patients with sepsis, so that the most notable differences between two groups of participants were found for the activity of superoxide dismutase (SOD) (p = 0.004). Comet assay indicated that patients with sepsis had significantly higher GDI compared to healthy subjects (p < 0.001), which positively correlated with the concentration of superoxide anion radical (О2-) (r = 0.497, p = 0.010), and nitrites (NО2-) (r = 0.473, p = 0.015), as well with the concentration of C reactive protein (CRP) (r = 0.460, p = 0.041). Regression analysis confirmed that patients' age (p = 0.033), the level of О2- (p = 0.007), CRP concentration (p = 0.029) and GDI (p = 0.001) increased the risk of lethal outcome in critically ill patients with sepsis. In conclusion, critically ill patients with sepsis have a higher degree of oxidative stress and inflammation which contribute to a higher level of DNA damage. Consequently, above mentioned parameters, including patients' age, adversely affect the outcome of critically ill patients with sepsis.
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Affiliation(s)
- Olgica Mihaljevic
- University of Kragujevac, Faculty of Medical Sciences, Department of Pathophysiology, Serbia.
| | | | - Danijela Jovanovic
- University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Serbia; University Clinical Center Kragujevac, Serbia
| | - Svetlana Miletic Drakulic
- University Clinical Center Kragujevac, Serbia; University of Kragujevac, Faculty of Medical Sciences, Department of Neurology, Serbia
| | | | - Aleksandra Markovic
- University of Kragujevac, Faculty of Sciences, Department of Biology, Serbia
| | - Marijana Stanojevic Pirkovic
- University Clinical Center Kragujevac, Serbia; University of Kragujevac, Faculty of Medical Sciences, Department of Biochemistry, Serbia
| | - Ivan Srejovic
- University of Kragujevac, Faculty of Medical Sciences, Department of Physiology, Serbia
| | - Vladimir Jakovljevic
- University of Kragujevac, Faculty of Medical Sciences, Department of Physiology, Serbia
| | - Olivera Milosevic-Djordjevic
- University of Kragujevac, Faculty of Sciences, Department of Biology, Serbia; University of Kragujevac, Faculty of Medical Sciences, Department of Genetics, Serbia
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Yin L, Tang Y, Lin X, Jiang B. Progress in the mechanism of mitochondrial dysfunction in septic cardiomyopathy. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2156622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Leijing Yin
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China
- Sepsis Translational Medicine Key Lab of Hunan Province, Hunan, People’s Republic of China
- National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, People’s Republic of China
| | - Yuting Tang
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China
- Sepsis Translational Medicine Key Lab of Hunan Province, Hunan, People’s Republic of China
- National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, People’s Republic of China
| | - Xiaofang Lin
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China
- Sepsis Translational Medicine Key Lab of Hunan Province, Hunan, People’s Republic of China
- National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, People’s Republic of China
| | - Bimei Jiang
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China
- Sepsis Translational Medicine Key Lab of Hunan Province, Hunan, People’s Republic of China
- National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan, People’s Republic of China
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10
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Gu WJ, Kong YJ, Li YJ, Wang CM. P(v-a)CO 2/C(a-v)O 2 as a red blood cell transfusion trigger and prognostic indicator for sepsis-related anaemia: protocol for a prospective cohort study. BMJ Open 2022; 12:e059454. [PMID: 36192101 PMCID: PMC9535211 DOI: 10.1136/bmjopen-2021-059454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
INTRODUCTION Red blood cell (RBC) transfusion primarily aims to improve oxygen transport and tissue oxygenation. The transfusion strategy based on haemoglobin concentration could not accurately reflect cellular metabolism. The ratio of venous-arterial carbon dioxide tension difference to arterial-venous oxygen content difference (P(v-a)CO2/C(a-v)O2) is a good indicator of cellular hypoxia. We aim to explore the influence of P(v-a)CO2/C(a-v)O2 as an RBC transfusion trigger on outcomes in septic shock patients. METHODS AND ANALYSIS The study is a single-centre prospective cohort study. We consecutively enrol adult septic shock patients requiring RBC transfusion at intensive care unit (ICU) admission or during ICU stay. P(v-a)CO2/C(a-v)O2 will be recorded before and 1 hour after each transfusion. The primary outcome is ICU mortality. Binary logistic regression analyses will be performed to detect the independent association between P(v-a)CO2/C(a-v)O2 and ICU mortality. A cut-off value for P(v-a)CO2/C(a-v)O2 will be obtained by maximising the Youden index with the receiver operator characteristic curve. According to this cut-off value, patients included will be divided into two groups: one with the P(v-a)CO2/C(a-v)O2 >cut-off and the other with the P(v-a)CO2/C(a-v)O2 ≤cut off. Differences in clinical outcomes between the two groups will be assessed after propensity matching. ETHICS AND DISSEMINATION The study has been approved by the Institutional Review Board of Affiliated Hospital of Weifang Medical University (wyfy-2021-ky-059). Findings will be disseminated through conference presentations and peer-reviewed journals. TRIAL REGISTRATION NUMBER ChiCTR2100051748.
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Affiliation(s)
- Wan-Jie Gu
- Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Yu-Jia Kong
- School of Public Health, Weifang Medical University, Weifang, Shandong Province, China
| | - Yun-Jie Li
- Department of Critical Care Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Chun-Mei Wang
- Department of Critical Care Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
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11
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Mallat J, Rahman N, Hamed F, Hernandez G, Fischer MO. Pathophysiology, mechanisms, and managements of tissue hypoxia. Anaesth Crit Care Pain Med 2022; 41:101087. [PMID: 35462083 DOI: 10.1016/j.accpm.2022.101087] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 11/01/2022]
Abstract
Oxygen is needed to generate aerobic adenosine triphosphate and energy that is required to support vital cellular functions. Oxygen delivery (DO2) to the tissues is determined by convective and diffusive processes. The ability of the body to adjust oxygen extraction (ERO2) in response to changes in DO2 is crucial to maintain constant tissue oxygen consumption (VO2). The capability to increase ERO2 is the result of the regulation of the circulation and the effects of the simultaneous activation of both central and local factors. The endothelium plays a crucial role in matching tissue oxygen supply to demand in situations of acute drop in tissue oxygenation. Tissue oxygenation is adequate when tissue oxygen demand is met. When DO2 is severely compromised, a critical DO2 value is reached below which VO2 falls and becomes dependent on DO2, resulting in tissue hypoxia. The different mechanisms of tissue hypoxia are circulatory, anaemic, and hypoxic, characterised by a diminished DO2 but preserved capacity of increasing ERO2. Cytopathic hypoxia is another mechanism of tissue hypoxia that is due to impairment in mitochondrial respiration that can be observed in septic conditions with normal overall DO2. Sepsis induces microcirculatory alterations with decreased functional capillary density, increased number of stopped-flow capillaries, and marked heterogeneity between the areas with large intercapillary distance, resulting in impairment of the tissue to extract oxygen and to satisfy the increased tissue oxygen demand, leading to the development of tissue hypoxia. Different therapeutic approaches exist to increase DO2 and improve microcirculation, such as fluid therapy, transfusion, vasopressors, inotropes, and vasodilators. However, the effects of these agents on microcirculation are quite variable.
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Affiliation(s)
- Jihad Mallat
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA; Normandy University, UNICAEN, ED 497, Caen, France.
| | - Nadeem Rahman
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Fadi Hamed
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Glenn Hernandez
- Departamento de Medicina Intensiva, Facultad de Medicina, Pontifcia Universidad Católica de Chile, Santiago, Chile
| | - Marc-Olivier Fischer
- Department of Anaesthesiology-Resuscitation and Perioperative Medicine, Normandy University, UNICAEN, Caen University Hospital, Normandy, Caen, France
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12
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Mitochondrial Sirt3 serves as a biomarker for sepsis diagnosis and mortality prediction. Sci Rep 2022; 12:10414. [PMID: 35729330 PMCID: PMC9213502 DOI: 10.1038/s41598-022-14365-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/06/2022] [Indexed: 11/08/2022] Open
Abstract
The purpose of this study is to determine whether the levels of serum Sirt3 correlate with disease severity and perfusion indicators in septic patients, as well as to assess the clinical value of Sirt3 as a potential novel marker for sepsis diagnosis and mortality prediction. A total of 79 patients in the ICU were included in the study, of which 28 were postoperatively noninfectious and the remaining 51 patients were all diagnosed with sepsis during the study period. The levels of Sirt3 were detected and dynamically monitored by enzyme-linked adsorption method, Pearson or Spearman coefficient for correlation analysis between Sirt3 and clinical indicators, ROC curve for evaluation of diagnosis and mortality prediction, Kaplan-Meier method for the significance of Sirt3 in 28-day survival. The serum levels of Sirt3 were lower in the sepsis patients on day 1 (P < 0.0001), and the septic shock group had lower Sirt3 levels than the sepsis group (P = 0.013). Sirt3 had good negative correlations with SOFA scores both in sepsis and septic shock groups (Pearson: r2 = - 0.424, - 0.518; P = 0.011, 0.040), and Sirt3 correlated strongly with ScvO2 in the septic shock group (Pearson: r2 = - 0.679, P = 0.004) and with PCT in the sepsis group (Pearson: r2 = - 0.409, P = 0.015). Sirt3 not only performed well in identifying sepsis (AUC = 0.995, 95% CI 0.987-1, P < 0.0001) but also greatly enhanced lactate's specificity in detecting septic shock (from 91.43 to 94.29%). Patients in the low Sirt3 group had higher ScvO2, lactate, APACHE II score, SOFA score, longer ICU stays, and worse indicators of inflammation (TNF-α, IL-6) and infection (PCT) than those in the high Sirt3 group (P < 0.05). Additionally, Sirt3 can predict mortality of sepsis (AUC = 0.746, 95% CI 0.571-0.921, P = 0.022), patients with serum Sirt3 < 10.07 pg/ml have a lower 28-day survival (log-rank P = 0.008). Low serum levels of Sirt3 are significantly correlated with the disease severity. At the same time, Sirt3 increases the sensitivity of lactate to detect "cellular hypoxia" in septic shock. Sirt3 is a promising biomarker for the diagnosis of sepsis and predicting mortality risk in septic patients.
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13
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Mokhtari B, Yavari R, Badalzadeh R, Mahmoodpoor A. An Overview on Mitochondrial-Based Therapies in Sepsis-Related Myocardial Dysfunction: Mitochondrial Transplantation as a Promising Approach. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2022; 2022:3277274. [PMID: 35706715 PMCID: PMC9192296 DOI: 10.1155/2022/3277274] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 05/05/2022] [Indexed: 11/19/2022]
Abstract
Sepsis is defined as a life-threatening organ failure due to dysregulated host response to infection. Despite current advances in our knowledge about sepsis, it is still considered as a major global health challenge. Myocardial dysfunction is a well-defined manifestation of sepsis which is related to worse outcomes in septic patients. Given that the heart is a mitochondria-rich organ and the normal function of mitochondria is essential for successful modulation of septic response, the contribution of mitochondrial damage in sepsis-related myocardial dysfunction has attracted the attention of many scientists. It is widely accepted that mitochondrial damage is involved in sepsis-related myocardial dysfunction; however, effective and potential treatment modalities in clinical setting are still lacking. Mitochondrial-based therapies are potential approaches in sepsis treatment. Although various therapeutic strategies have been used for mitochondrial function improvement, their effects are limited when mitochondria undergo irreversible alterations under septic challenge. Therefore, application of more effective approaches such as mitochondrial transplantation has been suggested. This review highlights the crucial role of mitochondrial damage in sepsis-related myocardial dysfunction, then provides an overview on mitochondrial-based therapies and current approaches to mitochondrial transplantation as a novel strategy, and proposes future directions for more researches in this field.
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Affiliation(s)
- Behnaz Mokhtari
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rana Yavari
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Badalzadeh
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ata Mahmoodpoor
- Intensive Care Unit, Emam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
- Evidence-Based Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Haertel F, Reisberg D, Peters M, Nuding S, Schulze PC, Werdan K, Ebelt H. Predicting the Need for Renal Replacement Therapy Using a Vascular Occlusion Test and Tissue Oxygen Saturation in Patients in the Early Phase of Multiorgan Dysfunction Syndrome. J Clin Med 2022; 11:jcm11051420. [PMID: 35268511 PMCID: PMC8911273 DOI: 10.3390/jcm11051420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/19/2022] [Accepted: 03/02/2022] [Indexed: 11/25/2022] Open
Abstract
Background: Acute kidney injury (AKI) is associated with an increased mortality in critically ill patients, especially in patients with multiorgan dysfunction syndrome (MODS). In daily clinical practice, the grading of AKI follows the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. In most cases, a relevant delay occurs frequently between the onset of AKI and detectable changes in creatinine levels as well as clinical symptoms. The aim of the present study was to examine whether a near infrared spectroscopy (NIRS)-based, non-invasive ischemia–reperfusion test (vascular occlusion test (VOT)) together with unprovoked (under resting conditions) tissue oxygen saturation (StO2) measurements, contain prognostic information in the early stage of MODS regarding the developing need for renal replacement therapy (RRT). Methods: Within a period of 18 months, patients at the medical intensive care unit of a tertiary university hospital with newly developed MODS (≤24 h after diagnosis, APACHE II score ≥20) were included in our study. The VOT occlusion slope (OS) and recovery slope (RS) were recorded in addition to unprovoked StO2. StO2 was determined non-invasively in the area of the thenar muscles using a bedside NIRS device. The VOT was carried out by inflating a blood pressure cuff on the upper arm. AKI stages were determined by the changes in creatinine levels, urinary output, and/or the need for RRT according to KDIGO. Results: 56 patients with MODS were included in the study (aged 62.5 ± 14.4 years, 40 men and 16 women, APACHE II score 34.5 ± 6.4). Incidences of the different AKI stages were: no AKI, 16.1% (n = 9); AKI stage I, 19.6% (n = 11); AKI stage II, 25% (n = 14); AKI stage III, 39.3% (n = 22). Thus, 39.3% of the patients (n = 22) developed the need for renal replacement therapy (AKI stage III). These patients had a significantly higher mortality over 28 days (RRT, 72% (n = 16/22) vs. no RRT, 44% (n = 15/34); p = 0.03). The mean unprovoked StO2 of all patients at baseline was 81.7 ± 11.1%, and did not differ between patients with or without the need for RRT. Patients with RRT showed significantly weaker negative values of the OS (−9.1 ± 3.7 vs. −11.7 ± 4.1%/min, p = 0.01) and lower values for the RS (1.7 ± 0.9 vs. 2.3 ± 1.6%/s, p = 0.02) compared to non-dialysis patients. Consistent with these results, weaker negative values of the OS were found in higher AKI stages (no AKI, −12.7 ± 4.1%/min; AKI stage I, −11.5 ± 3.0%/min; AKI stage II, −11.1 ± 3.3%/min; AKI stage III, −9.1 ± 3.7%/min; p = 0.021). Unprovoked StO2 did not contain prognostic information regarding the AKI stages. Conclusions: The weaker negative values of the VOT parameter OS are associated with an increased risk of developing AKI and RRT, and increased mortality in the early phase of MODS, while unprovoked StO2 does not contain prognostic information in that regard.
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Affiliation(s)
- Franz Haertel
- Klinik für Innere Medizin I, Universitaetsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany;
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
- Correspondence: ; Tel.: +49-3641-9324-554
| | - Diana Reisberg
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
- Klinik für Pädiatrie, Ameos Klinikum Aschersleben, Eislebener Str. 7A, 06449 Aschersleben, Germany
| | - Martin Peters
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
- Klinik für Innere Medizin, Helios Klinikum Jerichower Land, August-Bebel-Str. 55a, 39288 Burg, Germany
| | - Sebastian Nuding
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
- Klinik für Innere Medizin II, Krankenhaus “St. Elisabeth”, Mauerstr. 5, 06110 Halle (Saale), Germany
| | - P. Christian Schulze
- Klinik für Innere Medizin I, Universitaetsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany;
| | - Karl Werdan
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
| | - Henning Ebelt
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
- Klinik für Innere Medizin II, Katholisches Krankenhaus “St. Johann Nepomuk”, Haarbergstr. 72, 99097 Erfurt, Germany
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Gandhirajan A, Roychowdhury S, Vachharajani V. Sirtuins and Sepsis: Cross Talk between Redox and Epigenetic Pathways. Antioxidants (Basel) 2021; 11:antiox11010003. [PMID: 35052507 PMCID: PMC8772830 DOI: 10.3390/antiox11010003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/09/2021] [Accepted: 12/11/2021] [Indexed: 12/19/2022] Open
Abstract
Sepsis and septic shock are the leading causes of death among hospitalized patients in the US. The immune response in sepsis transitions from a pro-inflammatory and pro-oxidant hyper-inflammation to an anti-inflammatory and cytoprotective hypo-inflammatory phase. While 1/3rd sepsis-related deaths occur during hyper-, a vast majority of sepsis-mortality occurs during the hypo-inflammation. Hyper-inflammation is cytotoxic for the immune cells and cannot be sustained. As a compensatory mechanism, the immune cells transition from cytotoxic hyper-inflammation to a cytoprotective hypo-inflammation with anti-inflammatory/immunosuppressive phase. However, the hypo-inflammation is associated with an inability to clear invading pathogens, leaving the host susceptible to secondary infections. Thus, the maladaptive immune response leads to a marked departure from homeostasis during sepsis-phases. The transition from hyper- to hypo-inflammation occurs via epigenetic programming. Sirtuins, a highly conserved family of histone deacetylators and guardians of homeostasis, are integral to the epigenetic programming in sepsis. Through their anti-inflammatory and anti-oxidant properties, the sirtuins modulate the immune response in sepsis. We review the role of sirtuins in orchestrating the interplay between the oxidative stress and epigenetic programming during sepsis.
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Affiliation(s)
- Anugraha Gandhirajan
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (A.G.); (S.R.)
| | - Sanjoy Roychowdhury
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (A.G.); (S.R.)
| | - Vidula Vachharajani
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (A.G.); (S.R.)
- Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Correspondence:
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Sobhy E, Kader RA, Aboulfotouh A, Eshra M, Sayed M. Associations of measured resting energy expenditure with predictive equations, NUTRIC score, and patient outcomes. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2021; 33:35. [PMID: 34690491 PMCID: PMC8520770 DOI: 10.1186/s43162-021-00060-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/26/2021] [Indexed: 11/12/2022] Open
Abstract
Background Indirect calorimetry is the reference method for measuring resting energy expenditure (REE), but the necessary equipment and technical expertise are not always available. Meanwhile, the NUTrition Risk in the Critically ill (NUTRIC) scale is designed to identify patients who would benefit from nutrition therapy, but no data are available regarding the association of NUTRIC scores with REE. Several predictive formulas are available as alternatives to indirect calorimetry for calculation of energy requirements, but they have not been compared in a homogeneous group of critically ill patients. The purpose of the study is to examine the correlations between energy expenditure and NUTRIC scores or patient outcomes, and to compare measured REE with estimations of energy expenditure. Methods In this observational, prospective study, indirect calorimetry was performed on 50 mechanically ventilated patients. Energy expenditure was also estimated with the bodyweight-based, Faisy–Fagon, and Penn-State PSUm equations. Results REE was higher in patients who survived treatment than in those who died, and was positively correlated with length of stay and duration of ventilation. NUTRIC scores did not correlate with REE. The Faisy–Fagon equation overestimated expenditure, whereas PSUm was unbiased and accurate. Calculations based on 25 kcal/kg bodyweight/day overestimated expenditure, whereas 23 kcal/kg/day produced unbiased estimates with greater accuracy than PSUm. Conclusion REE was positively associated with patient outcomes. Energy expenditure was accurately predicted by calculations of 23 kcal/kg bodyweight/day.
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Affiliation(s)
- Elham Sobhy
- Internal Medicine Department, KasrAlainy Cairo University, Cairo, Egypt
| | - Radwa Abdel Kader
- Internal Medicine Department, KasrAlainy Cairo University, Cairo, Egypt
| | | | - Mohammed Eshra
- Physiology Department, KasrAlainy Cairo University, Cairo, Egypt
| | - Mohamed Sayed
- Internal Medicine Department, KasrAlainy Cairo University, Cairo, Egypt.,Giza, Egypt
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Valeanu L, Bubenek-Turconi SI, Ginghina C, Balan C. Hemodynamic Monitoring in Sepsis-A Conceptual Framework of Macro- and Microcirculatory Alterations. Diagnostics (Basel) 2021; 11:1559. [PMID: 34573901 PMCID: PMC8469937 DOI: 10.3390/diagnostics11091559] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/22/2021] [Accepted: 08/26/2021] [Indexed: 12/29/2022] Open
Abstract
Circulatory failure in sepsis is common and places a considerable burden on healthcare systems. It is associated with an increased likelihood of mortality, and timely recognition is a prerequisite to ensure optimum results. While there is consensus that aggressive source control, adequate antimicrobial therapy and hemodynamic management constitute crucial determinants of outcome, discussion remains about the best way to achieve each of these core principles. Sound cardiovascular support rests on tailored fluid resuscitation and vasopressor therapy. To this end, an overarching framework to improve cardiovascular dynamics has been a recurring theme in modern critical care. The object of this review is to examine the nature of one such framework that acknowledges the growing importance of adaptive hemodynamic support combining macro- and microhemodynamic variables to produce adequate tissue perfusion.
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Affiliation(s)
- Liana Valeanu
- 1st Department of Cardiovascular Anesthesiology and Intensive Care, “Prof. C. C. Iliescu” Emergency Institute for Cardiovascular Diseases, 258 Fundeni Road, 022328 Bucharest, Romania; (L.V.); (S.-I.B.-T.)
- Department of Anesthesiology and Intensive Care, University of Medicine and Pharmacy “Carol Davila”, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Serban-Ion Bubenek-Turconi
- 1st Department of Cardiovascular Anesthesiology and Intensive Care, “Prof. C. C. Iliescu” Emergency Institute for Cardiovascular Diseases, 258 Fundeni Road, 022328 Bucharest, Romania; (L.V.); (S.-I.B.-T.)
- Department of Anesthesiology and Intensive Care, University of Medicine and Pharmacy “Carol Davila”, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Carmen Ginghina
- 3rd Department of Cardiology, “Prof. C. C. Iliescu” Emergency Institute for Cardiovascular Diseases, 258 Fundeni Road, 022328 Bucharest, Romania;
- Department of Cardiology, University of Medicine and Pharmacy “Carol Davila”, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Cosmin Balan
- 1st Department of Cardiovascular Anesthesiology and Intensive Care, “Prof. C. C. Iliescu” Emergency Institute for Cardiovascular Diseases, 258 Fundeni Road, 022328 Bucharest, Romania; (L.V.); (S.-I.B.-T.)
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Pravda J. Sepsis: Evidence-based pathogenesis and treatment. World J Crit Care Med 2021; 10:66-80. [PMID: 34316443 PMCID: PMC8291008 DOI: 10.5492/wjccm.v10.i4.66] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/13/2021] [Accepted: 06/02/2021] [Indexed: 02/06/2023] Open
Abstract
Sepsis can develop during the body’s response to a critical illness leading to multiple organ failure, irreversible shock, and death. Sepsis has been vexing health care providers for centuries due to its insidious onset, generalized metabolic dysfunction, and lack of specific therapy. A common factor underlying sepsis is the characteristic hypermetabolic response as the body ramps up every physiological system in its fight against the underlying critical illness. A hypermetabolic response requires supraphysiological amounts of energy, which is mostly supplied via oxidative phosphorylation generated ATP. A by-product of oxidative phosphorylation is hydrogen peroxide (H2O2), a toxic, membrane-permeable oxidizing agent that is produced in far greater amounts during a hypermetabolic state. Continued production of mitochondrial H2O2 can overwhelm cellular reductive (antioxidant) capacity leading to a build-up within cells and eventual diffusion into the bloodstream. H2O2 is a metabolic poison that can inhibit enzyme systems leading to organ failure, microangiopathic dysfunction, and irreversible septic shock. The toxic effects of H2O2 mirror the clinical and laboratory abnormalities observed in sepsis, and toxic levels of blood H2O2 have been reported in patients with septic shock. This review provides evidence to support a causal role for H2O2 in the pathogenesis of sepsis, and an evidence-based therapeutic intervention to reduce H2O2 levels in the body and restore redox homeostasis, which is necessary for normal organ function and vascular responsiveness.
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Affiliation(s)
- Jay Pravda
- Inflammatory Disease Research Centre, Therashock LLC, Palm Beach Gardens, FL 33410, United States
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19
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David OM, Olanlokun JO, Owoniyi BE, Ayeni M, Ebenezer O, Koorbanally NA. Studies on the mitochondrial, immunological and inflammatory effects of solvent fractions of Diospyros mespiliformis Hochst in Plasmodium berghei-infected mice. Sci Rep 2021; 11:6941. [PMID: 33767260 PMCID: PMC7994402 DOI: 10.1038/s41598-021-85790-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 03/05/2021] [Indexed: 01/31/2023] Open
Abstract
The use of medicinal plants in the treatment of malaria is gaining global attention due to their efficacy and cost effectiveness. This study evaluated the bioactivity-guided antiplasmodial efficacy and immunomodulatory effects of solvent fractions of Diospyros mespiliformis in mice infected with a susceptible strain of Plasmodium berghei (NK 65). The crude methanol extract of the stem of D. mespiliformis (DM) was partitioned between n-hexane, dichloromethane, ethyl acetate and methanol. Male Swiss mice (20 ± 2 g) infected with P. berghei were grouped and treated with vehicle (10 mL/kg, control), Artemether lumefantrine (10 mg/kg), 100, 200 and 400 mg/kg of n-hexane, dichloromethane, ethyl acetate and methanol fractions of D. mespiliformis for seven days. Blood was obtained for heme and hemozoin contents while serum was obtained for inflammatory cytokines and immunoglobulins G and M assessments. Liver mitochondria were isolated for mitochondrial permeability transition (mPT), mitochondrial F1F0 ATPase (mATPase) and lipid peroxidation (mLPO) assays. The GC-MS was used to identify the compounds present in the most potent fraction. The dichloromethane fraction had the highest parasite clearance and improved hematological indices relative to the drug control. The heme values increased, while the hemozoin content significantly (P < 0.05) decreased compared with the drug control. The highest dose of HF and MF opened the mPT pore while the reversal effects of DF on mPT, mATPase and mLPO were dose-dependent. The levels of IgG, IgM and TNFα in the DF group were significantly higher than the drug control, while the IL-1β and IL-6 values did not vary linearly with the dose. Lupeol and Stigmastan-3,5-diene were the most abundant phytochemicals in the DF. The outcome of this study showed that the DF has immunomodulatory effects in infected mice, reduced proliferation of the malaria parasite and thus protect liver cells.
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Affiliation(s)
| | - John Oludele Olanlokun
- Laboratories for Biomembrane Research and Biotechnology, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan, Nigeria.
| | | | - MoyinOluwa Ayeni
- Department of Microbiology, Ekiti State University, Ado-Ekiti, Nigeria
| | - Oluwakemi Ebenezer
- School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa
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20
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Andreis DT, Mallat J, Tettamanti M, Chiarla C, Giovannini I, Gatti S, Protti A. Increased ratio of P[v-a]CO 2 to C[a-v]O 2 without global hypoxia: the case of metformin-induced lactic acidosis. Respir Physiol Neurobiol 2021; 285:103586. [PMID: 33202296 DOI: 10.1016/j.resp.2020.103586] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/18/2020] [Accepted: 11/11/2020] [Indexed: 12/24/2022]
Abstract
The ratio of venoarterial CO2 tension to arteriovenous O2 content difference (P[v-a]CO2/C[a-v]O2) increases when lactic acidosis is due to inadequate oxygen supply (hypoxia); we aimed to verify whether it also increases when lactic acidosis develops because of mitochondrial dysfunction (dysoxia) with constant oxygen delivery. Twelve anaesthetised, mechanically ventilated pigs were intoxicated with IV metformin (4.0 to 6.4 g over 2.5 to 4.0 h). Saline and norepinephrine were used to preserve oxygen delivery. Lactate and P[v-a]CO2/C[a-v]O2 were measured every one or two hours (arterial and mixed venous blood). During metformin intoxication, lactate increased from 0.8 (0.6-0.9) to 8.5 (5.0-10.9) mmol/l (p < 0.001), even if oxygen delivery remained constant (from 352 ± 78 to 343 ± 97 ml/min, p = 0.098). P[v-a]CO2/C[a-v]O2 increased from 1.6 (1.2-1.8) to 2.3 (1.9-3.2) mmHg/ml/dl (p = 0.004). The intraclass correlation coefficient between lactate and P[v-a]CO2/C[a-v]O2 was 0.72 (p < 0.001). We conclude that P[v-a]CO2/C[a-v]O2 increases when lactic acidosis is due to dysoxia. Therefore, a high P[v-a]CO2/C[a-v]O2 may not discriminate hypoxia from dysoxia as the cause of lactic acidosis.
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Affiliation(s)
- Davide T Andreis
- Department of Anaesthesia and Intensive Care Units, Humanitas Clinical and Research Center - IRCCS, Rozzano Milan, Italy
| | - Jihad Mallat
- Department of Critical Care Medicine, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates; Department of Anaesthesiology and Critical Care Medicine, Centre Hospitalier Du Dr. Schaffner, Lens Cedex, France
| | - Mauro Tettamanti
- Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri - IRCCS, Milan, Italy
| | - Carlo Chiarla
- CNR-IASI Center for the Pathophysiology of Shock and Biomathematics, Catholic University of the Sacred Heart School of Medicine, Rome, Italy
| | - Ivo Giovannini
- CNR-IASI Center for the Pathophysiology of Shock and Biomathematics, Catholic University of the Sacred Heart School of Medicine, Rome, Italy; Liver Transplant and General Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefano Gatti
- Center for Preclinical Research, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Alessandro Protti
- Department of Anaesthesia and Intensive Care Units, Humanitas Clinical and Research Center - IRCCS, Rozzano Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy.
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21
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Nicolescu LC, Nicolescu CM, Mihu AG, Balta C. The effect of red blood cell transfusion on peripheral tissue oxygen delivery and consumption in septic patients. Transfus Clin Biol 2020; 28:5-10. [PMID: 33307215 DOI: 10.1016/j.tracli.2020.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/30/2020] [Accepted: 12/01/2020] [Indexed: 10/22/2022]
Abstract
OBJECTIVES The impact of blood transfusion on tissue oxygen delivery (DO2) and tissue oxygen consumption (VO2) is a subject of current clinical studies. The primary objective of this observational study is to evaluate and measure the parameters involved in determining DO2 and VO2, in early phase of septic patients. A secondary objective of this study is to assess the potential benefit of blood transfusion on tissue metabolism by serial measurements of lactic acid (Ac. Lac.). MATERIAL AND METHODS A group of 29 patients were studied, each patient received between one to three units of fresh packed red blood cells (pRBC). Clinical and paraclinical criteria for sepsis as well as the plasma value of haemoglobin (Hb) below 10g/dL represented the inclusion criteria in this study. We evaluated Hb, haematocrit (HCT), arterial blood oxigen saturation (SAO2), central venous oxygen saturation (SCVO2), parameters which are involved in determination of DO2 and VO2, before and after the transfusion of one unit of pRBC. Values of Ac. Lac. were also assessed in order to determine the type of metabolism (aerobic or anaerobic). SCVO2, SAO2, Hb, HCT and Ac. Lac. were determined using Epoc blood analyser. The cardiac output (CO) and systemic vascular resistance (SVR) were monitored during blood transfusion, using Vigileo monitor (Edward's Life Science, PreSep catheter kit). SAO2 was also monitored by pulse-oximetry. RESULTS Changes in Hb, HCT and SCVO2 before and after pRBC transfusion (which further determine VO2) were statistically significant (P<0.001). A statistically significant increase (P<0.001) was obtained in Ac. Lac. values, before and after pRBC transfusion. SAO2 and CO directly involved in producing DO2, were clinically monitored during blood transfusion and the results remained constant. CONCLUSION Results obtained in this clinical study show an increase in DO2 in critically ill septic patients and also an increase in oxygen tissue uptake which is similar to VO2, clearly pointing out the benefit of pRBC transfusion. The benefits of pRBC transfusion on tissue metabolism in critically ill septic patients remain elusive because of lactic acid values increase during and after transfusion. Based on our findings we recommend that Hb values used as a single trigger for pRBC transfusion should be further studied and that additional parameters such as SCVO2 and lactic acid should be considered as possible triggers for transfusion. Values of Hb and HCT should never be neglected.
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Affiliation(s)
- L C Nicolescu
- Department of Public Health, Faculty of Medicine "Vasile Goldis" Western University, str. Liviu Rebreanu nr.86, 310048, Arad, Romania
| | - C M Nicolescu
- Department of Anesthesia and Intensive Care, Emergency County Hospital, Str. Andreny Karoly nr. 2-4, 310037, Arad, Romania.
| | - A G Mihu
- Department of Microbiology, Faculty of Medicine "Vasile Goldis" Western University, str. Liviu Rebreanu, nr. 86, 310048, Arad, Romania; Bioclinica, str. Dreptatii nr. 23,bl. 717, 310300, Arad, Romania
| | - C Balta
- Department of Experimental and Applied Biology, "Aurel Ardelean" Institute of Life Sciences, "Vasile Goldis" Western University, str. Liviu Rebreanu, nr. 86, 310048, Arad, Romania
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Asim M, Amin F, El-Menyar A. Multiple organ dysfunction syndrome: Contemporary insights on the clinicopathological spectrum. Qatar Med J 2020; 2020:22. [PMID: 33628712 PMCID: PMC7884906 DOI: 10.5339/qmj.2020.22] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 03/03/2020] [Indexed: 12/27/2022] Open
Abstract
Multiorgan dysfunction syndrome (MODS) remains a major complication and challenge to treat patients with critical illness in different intensive care unit settings. The exact mechanism and pathophysiology of MODS is complex and remains unexplored. We reviewed the literature from January 2011 to August 2019 to analyze the underlying mechanisms, prognostic factors, MODS scoring systems, organ systems dysfunctions, and the management of MODS. We used the search engines PubMed, MEDLINE, Scopus, and Google Scholar with the keywords "multiple organ dysfunction syndrome," "intensive care units," "multiorgan failure," "MODS scoring system," and "MODS management." The initial search yielded 3550 abstracts, of which 91 articles were relevant to the scope of the present article. A better understanding of a disease course will help differentiate the signs of an intense inflammatory response from the early onset of sepsis and minimize the inappropriate use of medications. This, in turn, will promote organtargeted therapy and prevent occurrence and progression of MODS.
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Affiliation(s)
- Mohammad Asim
- Department of Surgery, Clinical Research, Trauma Surgery Section, Hamad General Hospital, Doha, Qatar
| | - Farhana Amin
- Sri Ramaswamy Memorial Medical College Hospital & Research Center, Tamil Nadu, India
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Berger MM. Do micronutrient deficiencies contribute to mitochondrial failure in critical illness? Curr Opin Clin Nutr Metab Care 2020; 23:102-110. [PMID: 31972589 DOI: 10.1097/mco.0000000000000635] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Mitochondrial dysfunction seems to be the common denominator of several critical care conditions and particularly of sepsis. Faced with relative failure, and limited progress of sepsis therapies aiming at blocking some oxidative and/or inflammatory pathways, the question of antioxidants micronutrient therapy, particularly of selenium, ascorbic acid and thiamine remains open. RECENT FINDINGS The rationale for the essentiality of numerous micronutrients within the mitochondria is well established. Many studies have tested single micronutrients in animal and in-vitro models and provide positive evidences in favor of reduction of organ failure (cardiac and renal mainly). In clinical settings, high-dose selenium administration in sepsis has been disappointing. The most recent high dose, short-term ascorbic acid trial in sepsis is promising though, with an associated reduction of mortality, but analysis of the impact of this intervention on the various organs remains to be conducted. SUMMARY Results from animal and human studies indicate that there are indeed intervention options at the level of the mitochondria, but neither the optimal dose nor the optimal combination of micronutrients is yet identified.
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Affiliation(s)
- Mette M Berger
- Service of Adult Intensive Care, Lausanne University Hospital CHUV, Lausanne, Switzerland
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Abstract
Multiple organ dysfunction syndrome (MODS) is one of the most common syndromes of critical illness and the leading cause of mortality among critically ill patients. Multiple organ dysfunction syndrome is the clinical consequence of a dysregulated inflammatory response, triggered by clinically diverse factors with the main pillar of management being invasive organ support. During the last years, the advances in the clarification of the molecular pathways that trigger, mitigate, and determine the outcome of MODS have led to the increasing recognition of MODS as a distinct disease entity with distinct etiology, pathophysiology, and potential future therapeutic interventions. Given the lack of effective treatment for MODS, its early recognition, the early intensive care unit admission, and the initiation of invasive organ support remain the most effective strategies of preventing its progression and improving outcomes.
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Affiliation(s)
- Nicholas M Gourd
- Department of Intensive Care Medicine, Derriford Hospital, 6634University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom.,Faculty of Medicine and Dentistry, 6634University of Plymouth, Plymouth, United Kingdom
| | - Nikitas Nikitas
- Department of Intensive Care Medicine, Derriford Hospital, 6634University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom
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25
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Vico TA, Marchini T, Ginart S, Lorenzetti MA, Adán Areán JS, Calabró V, Garcés M, Ferrero MC, Mazo T, D’Annunzio V, Gelpi RJ, Corach D, Evelson P, Vanasco V, Alvarez S. Mitochondrial bioenergetics links inflammation and cardiac contractility in endotoxemia. Basic Res Cardiol 2019; 114:38. [DOI: 10.1007/s00395-019-0745-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 07/30/2019] [Indexed: 12/16/2022]
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Xu D, Liao S, Li P, Zhang Q, Lv Y, Fu X, Yang M, Wang J, Kong L. Metabolomics Coupled with Transcriptomics Approach Deciphering Age Relevance in Sepsis. Aging Dis 2019; 10:854-870. [PMID: 31440390 PMCID: PMC6675524 DOI: 10.14336/ad.2018.1027] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 10/27/2018] [Indexed: 12/12/2022] Open
Abstract
Sepsis is a severe disease frequently occurred in the Intenisive Care Unit (ICU), which has a very high morbidity and mortality, especially in patients aged over 65 years. Owing to the aging effect and the ensuing deterioration of body function, the elder patients may have atypical responses to sepsis. Diagnosis and pathogenesis of sepsis in this population are thus difficult, which hindered effective treatment and management in clinic. To investigated age effects on sepsis, 158 elderly septic patients and 71 non-septic elderly participants were enrolled, and their plasma samples were collected for transcriptomics (RNA-seq) and metabolomics (NMR and GC-MS) analyses, which are both increasingly being utilized to discover key molecular changes and potential biomarkers for various diseases. Protein-protein interaction (PPI) analysis was subsequently performed to assist cross-platform integration. Real time polymerase chain reaction (RT-PCR) was used for validation of RNA-seq results. For further understanding of the mechanisms, cecal ligation and puncture (CLP) experiment was performed both in young and middle-aged rats, which were subjected to NMR-based metabolomics study and validated for several key inflammation pathways by western blot. Comprehensive analysis of data from the two omics approaches provides a systematic perspective on dysregulated pathways that could facilitate the development of therapy and biomarkers for elderly sepsis. Additionally, the metabolites of lactate, arginine, histamine, tyrosine, glutamate and glucose were shown to be highly specific and sensitive in distinguishing septic patients from healthy controls. Significant increases of arginine, trimethylamine N-oxide and allantoin characterized elderly patient incurred sepsis. Further analytical and biological validations in different subpopulations of septic patients should be carried out, allowing accurate diagnostics and precise treatment of sepsis in clinic.
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Affiliation(s)
- Dingqiao Xu
- 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shanting Liao
- 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Pei Li
- 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qian Zhang
- 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yan Lv
- 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaowei Fu
- 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Minghua Yang
- 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Junsong Wang
- 2Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, China
| | - Lingyi Kong
- 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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27
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Reitsema VA, Star BS, de Jager VD, van Meurs M, Henning RH, Bouma HR. Metabolic Resuscitation Strategies to Prevent Organ Dysfunction in Sepsis. Antioxid Redox Signal 2019; 31:134-152. [PMID: 30403161 DOI: 10.1089/ars.2018.7537] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Significance: Sepsis is the main cause of death among patients admitted to the intensive care unit. As current treatment is limited to antimicrobial therapy and supportive care, mortality remains high, which warrants efforts to find novel therapies. Recent Advances: Mitochondrial dysfunction is emerging as a key process in the induction of organ dysfunction during sepsis, and metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis. Critical Issues: Here, we review novel strategies to maintain organ function in sepsis by precluding mitochondrial dysfunction by lowering energetic demand to allow preservation of adenosine triphosphate-levels, while reducing free radical generation. As the most common strategy to suppress metabolism, that is, cooling, does not reveal unequivocal beneficial effects and may even increase mortality, caloric restriction or modulation of energy-sensing pathways (i.e., sirtuins and AMP-activated protein kinase) may offer safe alternatives. Similar effects may be offered when mimicking hibernation by hydrogen sulfide (H2S). In addition H2S may also confer beneficial effects through upregulation of antioxidant mechanisms, similar to the other gasotransmitters nitric oxide and carbon monoxide, which display antioxidant and anti-inflammatory effects in sepsis. In addition, oxidative stress may be averted by systemic or mitochondria-targeted antioxidants, of which a wide range are able to lower inflammation, as well as reduce organ dysfunction and mortality from sepsis. Future Directions: Mitochondrial dysfunction plays a key role in the pathophysiology of sepsis. As a consequence, metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis.
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Affiliation(s)
- Vera A Reitsema
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Bastiaan S Star
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Vincent D de Jager
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Matijs van Meurs
- 2 Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Robert H Henning
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Hjalmar R Bouma
- 1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,3 Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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28
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Plotnikov EY, Pevzner IB, Zorova LD, Chernikov VP, Prusov AN, Kireev II, Silachev DN, Skulachev VP, Zorov DB. Mitochondrial Damage and Mitochondria-Targeted Antioxidant Protection in LPS-Induced Acute Kidney Injury. Antioxidants (Basel) 2019; 8:antiox8060176. [PMID: 31197113 PMCID: PMC6617298 DOI: 10.3390/antiox8060176] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/06/2019] [Accepted: 06/12/2019] [Indexed: 12/16/2022] Open
Abstract
Induced and frequently unwanted alterations in the mitochondrial structure and functions are a key component of the pathological cascade in many kidney pathologies, including those associated with acute damage. One of the principal pathogenic elements causing mitochondrial dysfunction in Acute Kidney Injury (AKI) is oxidative stress. After ischemia and nephrotoxic action of drugs, sepsis and systemic inflammation are the most frequent causes of AKI. As the kidney suffers from oxidative stress during sepsis, one of the most promising approaches to alleviate such damaging consequences is the use of antioxidants. Considering administration of lipopolysaccharide (LPS) as a model of sepsis, we demonstrate that the mitochondria of neonatal renal tissue are severely affected by LPS-induced AKI, with pathological ultrastructural changes observed in both the mitochondria of the renal tubular epithelium and the vascular endothelium. Upon mitochondrial damage, we evaluated the effect of the mitochondria-targeted antioxidant plastoquinol decylrhodamine 19 (SkQR1) on the development of acute renal failure in newborn rats associated with systemic inflammation induced by the administration of LPS. We found that SkQR1 administration 3 h before LPS led to decreased urinal expression of the AKI marker neutrophil gelatinase-associated lipocalin 2 (NGAL), in addition to a decrease in urea and creatinine levels in the blood. Additionally, an observed impairment of proliferative activity in the neonatal kidney caused by LPS treatment was also prevented by the treatment of rat pups with SkQR1. Thus, one of the key events for renal tissue damage in neonatal sepsis is an alteration in the structure and function of the mitochondria and the mitochondria-targeted antioxidant SkQR1 is an effective nephroprotective agent, which protects the neonatal kidney from sepsis-induced AKI.
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Affiliation(s)
- Egor Y Plotnikov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia.
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 11797, Russia.
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow 119991, Russia.
| | - Irina B Pevzner
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia.
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 11797, Russia.
| | - Ljubava D Zorova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia.
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 11797, Russia.
| | | | - Andrey N Prusov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia.
| | - Igor I Kireev
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia.
| | - Denis N Silachev
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia.
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 11797, Russia.
| | - Vladimir P Skulachev
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia.
| | - Dmitry B Zorov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia.
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Moscow 11797, Russia.
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Nwafor DC, Brichacek AL, Mohammad AS, Griffith J, Lucke-Wold BP, Benkovic SA, Geldenhuys WJ, Lockman PR, Brown CM. Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment. J Cent Nerv Syst Dis 2019; 11:1179573519840652. [PMID: 31007531 PMCID: PMC6456845 DOI: 10.1177/1179573519840652] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 01/21/2019] [Indexed: 12/17/2022] Open
Abstract
Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB's role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors.
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Affiliation(s)
- Divine C Nwafor
- Graduate Programs in Neuroscience, Department of Neuroscience, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
- Department of Neuroscience, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Allison L Brichacek
- Immunology and Microbial Pathogenesis, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
- Department of Microbiology, Immunology, and Cell Biology, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Afroz S Mohammad
- Department of Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Jessica Griffith
- Department of Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Brandon P Lucke-Wold
- Graduate Programs in Neuroscience, Department of Neuroscience, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Stanley A Benkovic
- Department of Neuroscience, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Werner J Geldenhuys
- Graduate Programs in Neuroscience, Department of Neuroscience, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Paul R Lockman
- Graduate Programs in Neuroscience, Department of Neuroscience, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, Morgantown, WV, USA
| | - Candice M Brown
- Graduate Programs in Neuroscience, Department of Neuroscience, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
- Department of Neuroscience, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
- Immunology and Microbial Pathogenesis, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
- Department of Microbiology, Immunology, and Cell Biology, School of Medicine, Health Sciences Center, West Virginia University, Morgantown, WV, USA
- Center for Basic and Translational Stroke Research, Rockefeller Neuroscience Institute, Health Sciences Center, West Virginia University, Morgantown, WV, USA
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30
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Abstract
BACKGROUND Microvascular hyperpermeability resulting from endothelial barrier dysfunction (EBD) is associated with worse clinical outcomes in trauma-induced hemorrhagic shock. We have previously shown that treatment with Tubastatin A (TubA), a histone deacetylase 6 inhibitor, improves outcomes in animal models of shock. In this study, we investigate whether TubA treatment may prevent trauma-related EBD. METHODS Wistar-Kyoto rats subjected to 40% hemorrhage were treated with TubA or vehicle control. Acute lung injury (ALI) was assessed histologically from tissues harvested 6 hours posthemorrhage. In vitro, human umbilical vein endothelial cells (HUVECs) were cultured in EGM BulletKit medium. Medium was exchanged for glucose-free Dulbecco's Modified Eagle Medium (0.5% fetal bovine serum) with or without TubA, and cells were placed in an anoxic chamber (5% CO2, 95% N2, 20-48 hours). Expression of acetylated tubulin and hypoxia-inducible factor 1α was measured by Western blot. Soluble Intercellular Adhesion Molecule-1 concentration within the medium, a marker of endothelial integrity, was determined using enzyme-linked immunosorbent assay. Monolayers were assessed for permeability via transwell assays using fluorescein isothiocyanate-labeled albumin. RESULTS Rats treated with TubA had significantly reduced ALI relative to vehicle control. In vitro, TubA significantly attenuated anoxia-induced hyperpermeability, hypoxia-inducible factor 1α expression, and glycocalyx shedding. CONCLUSIONS Our findings demonstrate that TubA prevents hemorrhage-induced ALI in rats. Additionally, we have shown that TubA prevents anoxia-induced EBD in vitro. Taken together, these results suggest that TubA could attenuate microvascular hyperpermeability related to hemorrhagic shock.
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31
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Li M, Yu H, Wang Y, Qin L, Sun W. Role of IRF4 in the Protection of Metformin-Mediated Sepsis Myocarditis. Dose Response 2019; 17:1559325819827436. [PMID: 30944551 PMCID: PMC6440069 DOI: 10.1177/1559325819827436] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 12/14/2018] [Accepted: 01/02/2019] [Indexed: 12/16/2022] Open
Abstract
AIMS Metformin has been shown to play a protective role in diabetes. However, we found that metformin could mediate myocardial protection. Given that protein kinase C eplison (PKCε) and interferon regulatory factor 4 (IRF4) are critical for cardioprotection signaling. And measurement of fluorescence resonance energy transfer (FRET) efficiency can be used to determine whether 2 fluorophores are within a certain distance of each other. So we sought to determine whether metformin promotes PKCε/IRF4 activation by FRET. METHODS AND RESULTS The study built a mouse septic myocarditis model by intraperitoneal injection of Escherichia coli; thus, it provides valuable experimental data for the diagnosis and treatment of septic myocarditis. And cellular model of cardiomyocyte damage from adult rat cardiacmyocytes or H9c2 cells was induced by lipopolysaccharide employed to examine PKCε by molecular, biochemical, and cellular imaging analysis. Life span of septic myocarditis mouse was significantly prolonged by metformin. Metformin also decreased transforming growth factor β level and increased interleukin-10 productions. The FRET analysis in H9c2 cells suggested that there is prominent FRET signal for PKCε along in mitochondrial by metformin. CONCLUSION We demonstrate that metformin promotes rapid association of PKCε with IRF4 at mitochondrial microdomain of cardiac myocytes and PKCε via direct molecular interaction with IRF4. This regulatory mechanism may play an important role in cardioprotection.
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Affiliation(s)
- Minghua Li
- Department of Cardiology in First Hospital, Jilin University, Changchun, China
| | - Hongmei Yu
- China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
| | - Yonglin Wang
- Yangling Demonstration Zone Hospital, Xianyang, Shaanxi, China
| | - Ling Qin
- Department of Cardiology in First Hospital, Jilin University, Changchun, China
| | - Wei Sun
- Institute of Pediatrics in First Hospital, Jilin University, Changchun, China
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Araujo DT, Felice VB, Meregalli AF, Friedman G. Value of Central Venous to Arterial CO 2 Difference after Early Goal-directed Therapy in Septic Shock Patients. Indian J Crit Care Med 2019; 23:449-453. [PMID: 31749552 PMCID: PMC6842832 DOI: 10.5005/jp-journals-10071-23262] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background and aims Venous to arterial difference of carbon dioxide (Pv–aCO2) tracks tissue blood flow. We aimed to evaluate if Pv–aCO2 measured from a superior central vein sample is a prognostic index (ICU length of stay, SOFA score, 28th mortality rate) just after early goal-directed therapy (EGDT)comparing its ICU admission values between patients with normal and abnormal (>6 mm Hg) Pv–aCO2. As secondary objectives, we evaluated the relationship of Pv–aCO2 with other variables of perfusion during the 24 hours that followed EGDT. Materials and methods Prospective observational study conducted in an academic ICU adult septic shock patients after a 6-hour complete EGTD. Hemodynamic measurements, arterial/central venous blood gases, and arterial lactate were obtained on ICU admission and after 6, 18 and 24 hours. Results Sixty patients were included. Admission Pv–aCO2 values showed no prognostic value. Admission Pv–aCO2 (ROC curve 0.527 [CI 95% 0.394 to 0.658]) values showed low specificity and sensitivity as predictors of mortality. There was a difference observed in the mean Pv–aCO2 between nonsurvivors (NS) and survivors (S) after 6 hours. Central venous oxygen saturation (ScvO2) and Pv–aCO2 showed significant correlation (R2 = –0.41, P < 0.0001). Patients with normal ScvO2 (>70%) and abnormal Pv–aCO2 (>6 mm Hg) showed higher SOFA scores. Normal Pv–aCO2 group cleared their lactate levels in comparison to the abnormal Pv–aCO2 group. Conclusion In septic shock, admission Pv–aCO2 after EGDT is not related to worse outcomes. An abnormal Pv–aCO2 along with a normal ScvO2 is related to organ dysfunction. How to cite this article Araujo DT, Felice VB, Meregalli AF, Friedman G. Value of Central Venous to Arterial CO2 Difference after Early Goal-directed Therapy in Septic Shock Patients. Indian J Crit Care Med 2019;23(10):449–453.
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Affiliation(s)
- David Theophilo Araujo
- Central ICU, Santa Casa Hospital, Porto Alegre, Rio Grande do Su, Brazil; Programa de Pós-graduação em Ciências Pneumológicas, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Su, Brazil
| | - Vinicius Brenner Felice
- Central ICU, Santa Casa Hospital, Porto Alegre, Rio Grande do Su, Brazil; Programa de Pós-graduação em Ciências Pneumológicas, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Su, Brazil
| | - Andre Felipe Meregalli
- Central ICU, Santa Casa Hospital, Porto Alegre, Rio Grande do Su, Brazil; Programa de Pós-graduação em Ciências Pneumológicas, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Su, Brazil
| | - Gilberto Friedman
- Central ICU, Santa Casa Hospital, Porto Alegre, Rio Grande do Su, Brazil; Programa de Pós-graduação em Ciências Pneumológicas, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Su, Brazil
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Zhang H, Feng YW, Yao YM. Potential therapy strategy: targeting mitochondrial dysfunction in sepsis. Mil Med Res 2018; 5:41. [PMID: 30474573 PMCID: PMC6260865 DOI: 10.1186/s40779-018-0187-0] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 11/08/2018] [Indexed: 12/21/2022] Open
Abstract
Recently, the definition of sepsis was concluded to be a life-threatening organ dysfunction caused by a dysregulated host response to infection. Severe patients always present with uncorrectable hypotension or hyperlactacidemia, which is defined as septic shock. The new definition emphasizes dysregulation of the host response and multiple organ dysfunction, which is partially attributed to metabolic disorders induced by energy crisis and oxidative stress. Mitochondria are a cellular organelle that are well known as the center of energy production, and mitochondrial damage or dysfunction is commonly induced in septic settings and is a predominant factor leading to a worse prognosis. In the present review, we determine the major mitochondrial disorders from morphology to functions in sepsis. In the following, several clinical or pre-clinical assays for monitoring mitochondrial function are demonstrated according to accumulated evidence, which is the first step of specific therapy targeting to modulate mitochondrial function. Accordingly, various reagents used for regulating mitochondrial enzyme activities and promoting biogenesis have been documented, among which mitochondria-targeted cation, TPP-conjugated antioxidants are the most valuable for future trials and clinical treatment to improve mitochondrial function as they may take advantage of the prognosis associated with septic complications.
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Affiliation(s)
- Hui Zhang
- Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Fucheng Road 51, Haidian District, Beijing, 100048, China
| | - Yong-Wen Feng
- Department of Critical Care Medicine, The Second People's Hospital of Shenzhen, Shenzhen, 518035, China
| | - Yong-Ming Yao
- Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Fucheng Road 51, Haidian District, Beijing, 100048, China.
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Su L, Tang B, Liu Y, Zhou G, Guo Q, He W, Wang C, Zhuang H, Jiang L, Qin L, Deng Q, Shuai W, Zhang L, Wang X, Su J, Ma S, Liu D, Long Y. P(v-a)CO2/C(a-v)O2-directed resuscitation does not improve prognosis compared with SvO2 in severe sepsis and septic shock: A prospective multicenter randomized controlled clinical study. J Crit Care 2018; 48:314-320. [PMID: 30278407 DOI: 10.1016/j.jcrc.2018.09.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 08/11/2018] [Accepted: 09/10/2018] [Indexed: 02/06/2023]
Abstract
PURPOSES The present study examined the value of P(v-a)CO2/C(a-v)O2 compared with ScvO2 as a target for clinical resuscitation of severe sepsis/septic shock. MATERIALS AND METHODS 228 patients were randomly divided into a P(v-a)CO2/C(a-v)O2-targeted and a ScvO2-targeted therapy group. The effects on hemodynamics, interventional intensity, and outcome were recorded and analyzed. RESULTS The mean arterial pressure (MAP) of the P(v-a)CO2/C(a-v)O2-targeted therapy group was significantly higher at 3 h, 12 h, 24 h, and 3 days (P < .05). The P(v-a)CO2/C(a-v)O2 of the ScvO2-targeted therapy group was significantly higher at each time point after resuscitation (P < .05). However, the CVP, lactate, urine output, ScvO2, and P(v-a)CO2 were not significantly improved. The P(v-a)CO2/C(a-v)O2-targeted therapy group used a smaller fluid volume and required fewer red blood cell transfusions and vasoactive drugs, but these results were also not significant. There were no differences between 28-day and 60-day mortality, APACHEII and SOFA scores, ICU length of stay, residence length of stay, number of days free of vasoactive drugs, or number of ventilator-free days. Post hoc tests revealed no significant differences between these two groups in 28-day survival. CONCLUSION P(v-a)CO2/C(a-v)O2-directed resuscitation did not improve prognosis compared with ScvO2 in severe sepsis and septic shock. ClinicalTrials.gov Identifier NCT01877798.
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Affiliation(s)
- Longxiang Su
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Bo Tang
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yaling Liu
- Department of Critical Care Medicine, Beijing Pinggu Hospital, Beijing 101200, China
| | - Guanhua Zhou
- Department of Critical Care Medicine, People's Hospital of Beijing Daxing District, Beijing 102628, China
| | - Qinghua Guo
- Department of Critical Care Medicine, People's Hospital of Beijing Daxing District, Beijing 102628, China
| | - Wei He
- Department of Critical Care Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Chunmei Wang
- Department of Critical Care Medicine, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Haizhou Zhuang
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100009, China
| | - Li Jiang
- Department of Critical Care Medicine, Fuxing Hospital, Capital Medical University, Beijing 100038, China
| | - Long Qin
- Department of Critical Care Medicine, Beijing Haidian Hospital, Beijing 100036, China
| | - Qun Deng
- Department of Critical Care Medicine, Chinese PLA General Affiliated First Hospital, Beijing 100000, China
| | - Weizheng Shuai
- Department of Critical Care Medicine, PLA Navy General Hospital, Beijing 100048, China
| | - Lina Zhang
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiaomeng Wang
- Department of Critical Care Medicine, Xuzhou Central Hospital, Xuzhou 221009, China
| | - Jie Su
- Department of Critical Care Medicine, Hebei Province Medical University Affiliated Fourth Hospital, Shijiazhuang 050000, China
| | - Siqing Ma
- Department of Critical Care Medicine, Qinghai Province People's Hospital, Xining 810007, China
| | - Dawei Liu
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yun Long
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
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Wesselink E, Koekkoek WAC, Grefte S, Witkamp RF, van Zanten ARH. Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence. Clin Nutr 2018; 38:982-995. [PMID: 30201141 DOI: 10.1016/j.clnu.2018.08.032] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 08/03/2018] [Accepted: 08/25/2018] [Indexed: 12/30/2022]
Abstract
Persistent physical impairment is frequently encountered after critical illness. Recent data point towards mitochondrial dysfunction as an important determinant of this phenomenon. This narrative review provides a comprehensive overview of the present knowledge of mitochondrial function during and after critical illness and the role and potential therapeutic applications of specific micronutrients to restore mitochondrial function. Increased lactate levels and decreased mitochondrial ATP-production are common findings during critical illness and considered to be associated with decreased activity of muscle mitochondrial complexes in the electron transfer system. Adequate nutrient levels are essential for mitochondrial function as several specific micronutrients play crucial roles in energy metabolism and ATP-production. We have addressed the role of B vitamins, ascorbic acid, α-tocopherol, selenium, zinc, coenzyme Q10, caffeine, melatonin, carnitine, nitrate, lipoic acid and taurine in mitochondrial function. B vitamins and lipoic acid are essential in the tricarboxylic acid cycle, while selenium, α-tocopherol, Coenzyme Q10, caffeine, and melatonin are suggested to boost the electron transfer system function. Carnitine is essential for fatty acid beta-oxidation. Selenium is involved in mitochondrial biogenesis. Notwithstanding the documented importance of several nutritional components for optimal mitochondrial function, at present, there are no studies providing directions for optimal requirements during or after critical illness although deficiencies of these specific micronutrients involved in mitochondrial metabolism are common. Considering the interplay between these specific micronutrients, future research should pay more attention to their combined supply to provide guidance for use in clinical practise. REVISION NUMBER: YCLNU-D-17-01092R2.
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Affiliation(s)
- E Wesselink
- Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
| | - W A C Koekkoek
- Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716, Ede, The Netherlands.
| | - S Grefte
- Human and Animal Physiology, Wageningen University, De Elst 1, 6708 DW, Wageningen, The Netherlands.
| | - R F Witkamp
- Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
| | - A R H van Zanten
- Department of Intensive Care Medicine, Gelderse Vallei Hospital, Willy Brandtlaan 10, 6716, Ede, The Netherlands.
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Nagar H, Piao S, Kim CS. Role of Mitochondrial Oxidative Stress in Sepsis. Acute Crit Care 2018; 33:65-72. [PMID: 31723865 PMCID: PMC6849061 DOI: 10.4266/acc.2018.00157] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 05/08/2018] [Indexed: 12/25/2022] Open
Abstract
Mitochondria are considered the power house of the cell and are an essential part of the cellular infrastructure, serving as the primary site for adenosine triphosphate production via oxidative phosphorylation. These organelles also release reactive oxygen species (ROS), which are normal byproducts of metabolism at physiological levels; however, overproduction of ROS under pathophysiological conditions is considered part of a disease process, as in sepsis. The inflammatory response inherent in sepsis initiates changes in normal mitochondrial functions that may result in organ damage. There is a complex system of interacting antioxidant defenses that normally function to combat oxidative stress and prevent damage to the mitochondria. It is widely accepted that oxidative stress-mediated injury plays an important role in the development of organ failure; however, conclusive evidence of any beneficial effect of systemic antioxidant supplementation in patients with sepsis and organ dysfunction is lacking. Nevertheless, it has been suggested that antioxidant therapy delivered specifically to the mitochondria may be useful.
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Affiliation(s)
- Harsha Nagar
- Department of Physiology, Chungnam National University School of Medicine, Daejeon, Korea
| | - Shuyu Piao
- Department of Physiology, Chungnam National University School of Medicine, Daejeon, Korea
| | - Cuk-Seong Kim
- Department of Physiology, Chungnam National University School of Medicine, Daejeon, Korea
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Thiamine as a Renal Protective Agent in Septic Shock. A Secondary Analysis of a Randomized, Double-Blind, Placebo-controlled Trial. Ann Am Thorac Soc 2018; 14:737-741. [PMID: 28207287 DOI: 10.1513/annalsats.201608-656bc] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
RATIONALE Acute kidney injury (AKI) is common in patients with sepsis and has been associated with high mortality rates. The provision of thiamine to patients with sepsis may reduce the incidence and severity of sepsis-related AKI and thereby prevent renal failure requiring renal replacement therapy (RRT). OBJECTIVES To test the hypothesis that thiamine supplementation mitigates kidney injury in septic shock. METHODS This was a secondary analysis of a single-center, randomized, double-blind trial comparing thiamine to placebo in patients with septic shock. Renal function, need for RRT, timing of hemodialysis catheter placement, and timing of RRT initiation were abstracted. The baseline creatinine and worst creatinine values between 3 and 24 hours, 24 and 48 hours, and 48 and 72 hours were likewise abstracted. RESULTS There were 70 patients eligible for analysis after excluding 10 patients in whom hemodialysis was initiated before study drug administration. Baseline serum creatinine in the thiamine group was 1.2 mg/dl (interquartile range, 0.8-2.5) as compared with 1.8 mg/dl (interquartile range, 1.3-2.7) in the placebo group (P = 0.3). After initiation of the study drug, more patients in the placebo group than in the thiamine group were started on RRT (eight [21%] vs. one [3%]; P = 0.04). In the repeated measures analysis adjusting for the baseline creatinine level, the worst creatinine levels were higher in the placebo group than in the thiamine group (P = 0.05). CONCLUSIONS In this post hoc analysis of a randomized controlled trial, patients with septic shock randomized to receive thiamine had lower serum creatinine levels and a lower rate of progression to RRT than patients randomized to placebo. These findings should be considered hypothesis generating and can be used as a foundation for further, prospective investigation in this area.
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Kim K, Choi HS, Chung SP, Kwon WY. Septic Shock. ESSENTIALS OF SHOCK MANAGEMENT 2018. [PMCID: PMC7121676 DOI: 10.1007/978-981-10-5406-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
For more than 20 years, sepsis has been defined as symptoms associated with the response to microorganism infection, which was more specifically called systemic inflammatory response syndrome (SIRS). With the evidence of organ failure, it was called severe sepsis, and this could lead to hypotension (septic shock). However, with the deep understanding of the pathophysiology of sepsis, sepsis has been known as both inflammatory and anti-inflammatory. Additionally, the classic use of SIRS could lead to overestimation of sepsis. For example, usual common cold could be identified as sepsis in classic definition. With this background, new sepsis definition, Sepsis 3, was introduced and sepsis was defined as a “life-threatening organ dysfunction caused by a dysregulated host response to infection.” The management of sepsis has been changed dramatically, with the development of Surviving Sepsis Campaign, which substantially increased the survival of sepsis. However, this is not with the help of a new drug, but the implementation of a treatment system. Unfortunately, no specific drug for sepsis has survived in clinical use even though many candidate drugs have been successfully investigated in preclinical setting, and this leads to the new approach to the sepsis.
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Shea EK, Dombrowski SC, Silverstein DC. Survival analysis of hypotensive cats admitted to an intensive care unit with or without hyperlactatemia: 39 cases (2005-2011). J Am Vet Med Assoc 2017; 250:887-893. [PMID: 28358631 DOI: 10.2460/javma.250.8.887] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To examine the association between blood lactate concentration and survival to hospital discharge in critically ill hypotensive cats. DESIGN Retrospective case series. ANIMALS 39 cats admitted to an intensive care unit of a university veterinary hospital between January 2005 and December 2011 for which blood lactate concentration was recorded ≤ 1 hour before or after a Doppler-derived arterial blood pressure measurement ≤ 90 mm Hg (ie, hypotension) was obtained. PROCEDURES Medical records of each cat were reviewed to assess survival to hospital discharge, illness severity, duration of hospitalization, age, body weight, and PCV. Results were compared between hypotensive cats with and without hyperlactatemia (blood lactate concentration ≥ 2.5 mmol/L). RESULTS 6 of 39 (15%) hypotensive cats survived to hospital discharge. Twelve (31%) cats were normolactatemic (blood lactate concentration < 2.5 mmol/L), and 27 (69%) were hyperlactatemic. Hypotensive cats with normolactatemia had a higher blood pressure and higher survival rate than hypotensive cats with hyperlactatemia. Five-day Kaplan-Meier survival rates were 57% for normolactatemic cats and 17% for hyperlactatemic cats. Age, body weight, duration of hospitalization, PCV, and illness severity did not differ significantly between hypotensive cats with and without hyperlactatemia. CONCLUSIONS AND CLINICAL RELEVANCE Hypotensive, normolactatemic cats in an intensive care unit had a significantly greater chance of survival to hospital discharge than their hyperlactatemic counterparts. Blood lactate concentration may be a useful prognostic indicator for this patient population when used in conjunction with other clinical and laboratory findings.
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Merz TM, Pereira AJ, Schürch R, Schefold JC, Jakob SM, Takala J, Djafarzadeh S. Mitochondrial function of immune cells in septic shock: A prospective observational cohort study. PLoS One 2017; 12:e0178946. [PMID: 28591158 PMCID: PMC5462395 DOI: 10.1371/journal.pone.0178946] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 05/22/2017] [Indexed: 12/14/2022] Open
Abstract
Background Reduced cellular ATP synthesis due to impaired mitochondrial function of immune cells may be a factor influencing the immune response in septic shock. We investigate changes in mitochondrial function and bioenergetics of human monocytes and lymphocyte subsets. Methods Thirty patients with septic shock were studied at ICU admission, after 24 and 48 hours, and after resolution of shock. Enzymatic activities of citrate synthase and mitochondrial complexes I, IV, and ATP synthase and ATP content of monocytes, T-cells and B-cells and pro-inflammatory (IL-1β and IL-6) and anti-inflammatory (IL-10) cytokine plasma concentrations were compared to samples from 20 healthy volunteers. Results Large variations in mitochondrial enzymatic activities of immune cells of septic patients were detected. In monocytes, maximum levels of citrate synthase activity in sepsis were significantly lower when compared to controls (p = 0.021). Maximum relative enzymatic activity (ratio relative to citrate synthase activity) of complex I (p<0.001), complex IV (p = 0.017) and ATP synthase (p<0.001) were significantly higher. In T-cells, maximum levels of citrate synthase (p = 0.583) and relative complex IV (p = 0.602) activity did not differ between patients and controls, whereas levels of relative complex I (p = 0.006) and ATP synthase (p = 0.032) were significantly higher in septic patients. In B-cells of patients, maximum levels of citrate synthase activity (p = 0.004) and relative complex I (p<0.001) were significantly higher, and mean levels of relative complex IV (p = 0.042) lower than the control values, whereas relative ATP synthase activity did not differ (p = 1.0). No significant difference in cellular ATP content was detected in any cell line (p = 0.142–0.519). No significant correlations between specific cytokines and parameters of mitochondrial enzymatic activities or ATP content were observed. Conclusions Significant changes of mitochondrial enzymatic activities occur in human peripheral blood immune cells in septic shock when compared to healthy controls. Assessed sub-types of immune cells showed differing patterns of regulation. Total ATP-content of human immune cells did not differ between patients in septic shock and healthy volunteers.
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Affiliation(s)
- Tobias M. Merz
- Department of Intensive Care Medicine, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland
- * E-mail:
| | - Adriano J. Pereira
- Department of Intensive Care Medicine, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland
| | - Roger Schürch
- Division of Statistics, Clinical Trials Unit, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Joerg C. Schefold
- Department of Intensive Care Medicine, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland
| | - Stephan M. Jakob
- Department of Intensive Care Medicine, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland
| | - Jukka Takala
- Department of Intensive Care Medicine, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland
| | - Siamak Djafarzadeh
- Department of Intensive Care Medicine, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland
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Allanki S, Dixit M, Thangaraj P, Sinha NK. Analysis and modelling of septic shock microarray data using Singular Value Decomposition. J Biomed Inform 2017; 70:77-84. [PMID: 28499953 DOI: 10.1016/j.jbi.2017.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 04/28/2017] [Accepted: 05/08/2017] [Indexed: 11/26/2022]
Abstract
Being a high throughput technique, enormous amounts of microarray data has been generated and there arises a need for more efficient techniques of analysis, in terms of speed and accuracy. Finding the differentially expressed genes based on just fold change and p-value might not extract all the vital biological signals that occur at a lower gene expression level. Besides this, numerous mathematical models have been generated to predict the clinical outcome from microarray data, while very few, if not none, aim at predicting the vital genes that are important in a disease progression. Such models help a basic researcher narrow down and concentrate on a promising set of genes which leads to the discovery of gene-based therapies. In this article, as a first objective, we have used the lesser known and used Singular Value Decomposition (SVD) technique to build a microarray data analysis tool that works with gene expression patterns and intrinsic structure of the data in an unsupervised manner. We have re-analysed a microarray data over the clinical course of Septic shock from Cazalis et al. (2014) and have shown that our proposed analysis provides additional information compared to the conventional method. As a second objective, we developed a novel mathematical model that predicts a set of vital genes in the disease progression that works by generating samples in the continuum between health and disease, using a simple normal-distribution-based random number generator. We also verify that most of the predicted genes are indeed related to septic shock.
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Affiliation(s)
- Srinivas Allanki
- Laboratory of Vascular Biology, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Building, Indian Institute of Technology Madras, Chennai 600 036, India.
| | - Madhulika Dixit
- Laboratory of Vascular Biology, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Building, Indian Institute of Technology Madras, Chennai 600 036, India
| | - Paul Thangaraj
- Department of Cardiothoracic Surgery, Apollo Hospital, Chennai 600 006, India
| | - Nandan Kumar Sinha
- Department of Aerospace Engineering, Indian Institute of Technology Madras, Chennai 600 036, India
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Minasyan H. Sepsis and septic shock: Pathogenesis and treatment perspectives. J Crit Care 2017; 40:229-242. [PMID: 28448952 DOI: 10.1016/j.jcrc.2017.04.015] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 03/06/2017] [Accepted: 04/08/2017] [Indexed: 12/12/2022]
Abstract
The majority of bacteremias do not develop to sepsis: bacteria are cleared from the bloodstream. Oxygen released from erythrocytes and humoral immunity kill bacteria in the bloodstream. Sepsis develops if bacteria are resistant to oxidation and proliferate in erythrocytes. Bacteria provoke oxygen release from erythrocytes to arterial blood. Abundant release of oxygen to the plasma triggers a cascade of events that cause: 1. oxygen delivery failure to cells; 2. oxidation of plasma components that impairs humoral regulation and inactivates immune complexes; 3. disseminated intravascular coagulation and multiple organs' failure. Bacterial reservoir inside erythrocytes provides the long-term survival of bacteria and is the cause of ineffectiveness of antibiotics and host immune reactions. Treatment perspectives that include different aspects of sepsis development are discussed.
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Schmoch T, Uhle F, Siegler BH, Fleming T, Morgenstern J, Nawroth PP, Weigand MA, Brenner T. The Glyoxalase System and Methylglyoxal-Derived Carbonyl Stress in Sepsis: Glycotoxic Aspects of Sepsis Pathophysiology. Int J Mol Sci 2017; 18:E657. [PMID: 28304355 PMCID: PMC5372669 DOI: 10.3390/ijms18030657] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 03/08/2017] [Accepted: 03/14/2017] [Indexed: 01/08/2023] Open
Abstract
Sepsis remains one of the leading causes of death in intensive care units. Although sepsis is caused by a viral, fungal or bacterial infection, it is the dysregulated generalized host response that ultimately leads to severe dysfunction of multiple organs and death. The concomitant profound metabolic changes are characterized by hyperglycemia, insulin resistance, and profound transformations of the intracellular energy supply in both peripheral and immune cells. A further hallmark of the early phases of sepsis is a massive formation of reactive oxygen (ROS; e.g., superoxide) as well as nitrogen (RNS; e.g., nitric oxide) species. Reactive carbonyl species (RCS) form a third crucial group of highly reactive metabolites, which until today have been not the focus of interest in sepsis. However, we previously showed in a prospective observational clinical trial that patients suffering from septic shock are characterized by significant methylglyoxal (MG)-derived carbonyl stress, with the glyoxalase system being downregulated in peripheral blood mononuclear cells. In this review, we give a detailed insight into the current state of research regarding the metabolic changes that entail an increased MG-production in septicemia. Thus, we point out the special role of the glyoxalase system in the context of sepsis.
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Affiliation(s)
- Thomas Schmoch
- Department of Anesthesiology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
| | - Florian Uhle
- Department of Anesthesiology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
| | - Benedikt H Siegler
- Department of Anesthesiology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
| | - Thomas Fleming
- Department of Medicine I and Clinical Chemistry, Heidelberg University Hospital, 69120 Heidelberg, Germany.
| | - Jakob Morgenstern
- Department of Medicine I and Clinical Chemistry, Heidelberg University Hospital, 69120 Heidelberg, Germany.
| | - Peter P Nawroth
- Department of Medicine I and Clinical Chemistry, Heidelberg University Hospital, 69120 Heidelberg, Germany.
| | - Markus A Weigand
- Department of Anesthesiology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
| | - Thorsten Brenner
- Department of Anesthesiology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
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Oxidative stress in sepsis: Pathophysiological implications justifying antioxidant co-therapy. Burns 2016; 43:471-485. [PMID: 28034666 DOI: 10.1016/j.burns.2016.09.023] [Citation(s) in RCA: 163] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 08/10/2016] [Accepted: 09/19/2016] [Indexed: 01/20/2023]
Abstract
Sepsis is one of the main causes of death among critically ill patients. Sepsis pathogenesis includes infection by gram-negative and gram-positive bacteria, fungi, or both; exacerbated inflammatory response; hypotension, with potential to cause vasodilatory shock; and lesser delivery of oxygen to tissues due to impairment of oxygen utilization by cells. The participation of reactive species and/or free radicals such as nitric oxide (NO), peroxynitrite (ONOO-), superoxide (O2-), hydrogen peroxide (H2O2), and hydroxyl radical (OH) has been reported to underlie these effects. Mitochondrial dysfunction is related to loss of inner membrane potential and inhibition of the mitochondrial electron transfer chain and FoF1-adenosine triphosphate-synthase, resulting in cellular energetic failure. In addition, overproduction of NO due to inducible nitric oxide synthase (iNOS) activity has been associated with harmful effects such as general vasodilatation and hypo-responsiveness to therapeutic vasoconstrictor agents. Considering that iNOS expression is regulated by nuclear factor-κB, which may be activated by ROS, antioxidants could inhibit the overexpression of iNOS in sepsis. In line with this, several antioxidants such as vitamins C and E, polyphenols, melatonin, β-glucan, N-acetylcysteine, mitochondrion-targeted antioxidants (MitoQ, MitoE, and peptides associated with dimethyltyrosine), selenium salts, and organoselenium compounds were effective in ameliorating oxidative stress in animal models of sepsis and in a number of clinical trials with septic patients.
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Abstract
Critical care medicine is a young specialty that has experienced an expansion of research efforts in the last decade. Many physiologic and therapeutic principles or “dogmas” have been challenged, resulting in major “shifts” and minor “drifts” in thinking. This article reviews the available literature about some of these important and sometimes controversial changes, with emphasis on the practical implications of the concepts. Specific areas discussed include supply-dependent oxygen consumption in critical illness, manipulation of the cytokine cascade in sepsis, ventilation in the acute respiratory distress syndrome (ARDS), blood transfusion in the critically ill, the concept of the multiple organ dysfunction syndrome (MODS), the need for nutritional support in the critically ill, and others. Many of the changes discussed involve the recognition that the host response to a severe insult is exceedingly complex, and the understanding of this response and the effects of it at a tissue and cellular level are incomplete. As a result, the ability to impact the outcome of sepsis and MODS has thus far been disappointing, with the possible exception of “lung-protective” ventilation. The final challenge in critical care medicine is to gain information that will allow the practitioner to better understand, prevent, and treat the complex events that result in organ and cellular dysfunction. Future changes in dogma are welcome if they help achieve these goals.
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Affiliation(s)
- Ari Robin Joffe
- Department of Pediatrics, University of Alberta Hospital, University of Alberta, Edmonton, Alberta, Canada.
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Hobai IA, Aziz K, Buys ES, Brouckaert P, Siwik DA, Colucci WS. Distinct Myocardial Mechanisms Underlie Cardiac Dysfunction in Endotoxemic Male and Female Mice. Shock 2016; 46:713-722. [PMID: 27405063 PMCID: PMC5110369 DOI: 10.1097/shk.0000000000000679] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In male mice, sepsis-induced cardiomyopathy develops as a result of dysregulation of myocardial calcium (Ca) handling, leading to depressed cellular Ca transients (ΔCai). ΔCai depression is partially due to inhibition of sarcoplasmic reticulum Ca ATP-ase (SERCA) via oxidative modifications, which are partially opposed by cGMP generated by the enzyme soluble guanylyl cyclase (sGC). Whether similar mechanisms underlie sepsis-induced cardiomyopathy in female mice is unknown.Male and female C57Bl/6J mice (WT), and mice deficient in the sGC α1 subunit activity (sGCα1), were challenged with lipopolysaccharide (LPS, ip). LPS induced mouse death and cardiomyopathy (manifested as the depression of left ventricular ejection fraction by echocardiography) to a similar degree in WT male, WT female, and sGCα1 male mice, but significantly less in sGCα1 female mice. We measured sarcomere shortening and ΔCai in isolated, externally paced cardiomyocytes, at 37°C. LPS depressed sarcomere shortening in both WT male and female mice. Consistent with previous findings, in male mice, LPS induced a decrease in ΔCai (to 30 ± 2% of baseline) and SERCA inhibition (manifested as the prolongation of the time constant of Ca decay, τCa, to 150 ± 5% of baseline). In contrast, in female mice, the depression of sarcomere shortening induced by LPS occurred in the absence of any change in ΔCai, or SERCA activity. This suggested that, in female mice, the causative mechanism lies downstream of the Ca transients, such as a decrease in myofilament sensitivity for Ca. The depression of sarcomere shortening shortening after LPS was less severe in female sGCα1 mice than in WT female mice, indicating that cGMP partially mediates cardiomyocyte dysfunction.These results suggest, therefore, that LPS-induced cardiomyopathy develops through distinct sex-specific myocardial mechanisms. While in males LPS induces sGC-independent decrease in ΔCai, in female mice LPS acts downstream of ΔCai, possibly via sGC-dependent myofilament dysfunction.
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Affiliation(s)
- Ion A Hobai
- *Cardiovascular Medicine, Department of Medicine, Boston University Medical Center, Boston, Massachusetts †Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard University, Boston, Massachusetts ‡Department of Biomedical Molecular Biology, Ghent University, and Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium
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Lim HS. Cardiogenic Shock: Failure of Oxygen Delivery and Oxygen Utilization. Clin Cardiol 2016; 39:477-83. [PMID: 27509355 DOI: 10.1002/clc.22564] [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] [Received: 03/10/2016] [Revised: 05/16/2016] [Indexed: 12/22/2022] Open
Abstract
Cardiogenic shock remains a highly lethal condition. Conventional therapy including revascularization and mechanical circulatory support aims to improve cardiac output and oxygen delivery, but increasing basic and clinical observations indicate wider circulatory and cellular abnormalities, particularly at the advanced stages of shock. Progressive cardiogenic shock is associated with microcirculatory and cellular abnormalities. Cardiogenic shock is initially characterized by a failure to maintain global oxygen delivery; however, progressive cardiogenic shock is associated with the release of pro-inflammatory cytokines, derangement of the regulation of regional blood flow, microcirculatory abnormalities, and cellular dysoxia. These abnormalities are analogous to septic shock and may not be reversed by increase in oxygen delivery, even to supranormal levels. Earlier mechanical circulatory support in cardiogenic shock may limit the development of microcirculatory and cellular abnormalities.
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Affiliation(s)
- Hoong Sern Lim
- Department of Cardiology, University Hospital Birmingham NHS Trust, Birmingham, United Kingdom
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Alvarez S, Vico T, Vanasco V. Cardiac dysfunction, mitochondrial architecture, energy production, and inflammatory pathways: Interrelated aspects in endotoxemia and sepsis. Int J Biochem Cell Biol 2016; 81:307-314. [PMID: 27477311 DOI: 10.1016/j.biocel.2016.07.032] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 07/22/2016] [Accepted: 07/27/2016] [Indexed: 10/21/2022]
Abstract
Septic patients with myocardial dysfunction have a 3-fold increase in mortality compared with patients without cardiovascular impairment, and usually show myocarditis, disruption of the contractile apparatus, increased amounts of interstitial collagen, and damaged mitochondria. The presence of nitric oxide and cytokines in cardiac tissue constitute the molecular markers and the intracellular messengers of inflammatory conditions in the heart due to the onset of sepsis and endotoxemia, derived from the nuclear factor-κB pathway activation and proinflammatory gene transcription. Sepsis occurs with an exacerbated inflammatory response that damages tissue mitochondria and impaired bioenergetic processes. The heart consumes 20-30 times its own weight in adenosine triphosphate every day, and 90% of this molecule is derived from mitochondrial oxidative phosphorylation. Cardiac energy management is comprised in sepsis and endotoxemia; both a deficit in energy production and alterations in the source of energy substrates are believed to be involved in impaired cardiac function. Although several hypotheses try to explain the molecular mechanisms underlying the complex condition of sepsis and endotoxemia, the current view is that these syndromes are the result of an intricate balance between prevailing levels of mitochondrial stress, biogenesis/autophagy signaling and mitochondria quality control processes, rather on a single factor. The aim of this review is to discuss current hypothesis of cardiac dysfunction related to energy metabolism and mitochondrial function in experimental models of sepsis and endotoxemia, and to introduce the importance of lipids (mainly cardiolipin) in the mechanism of cardiac energy mismanagement in these inflammatory conditions.
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Affiliation(s)
- Silvia Alvarez
- Institute of Biochemistry and Molecular Medicine (IBIMOL, UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956, C1113AAD Buenos Aires, Argentina.
| | - Tamara Vico
- Institute of Biochemistry and Molecular Medicine (IBIMOL, UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956, C1113AAD Buenos Aires, Argentina
| | - Virginia Vanasco
- Institute of Biochemistry and Molecular Medicine (IBIMOL, UBA-CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956, C1113AAD Buenos Aires, Argentina
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Joffe A, Anton N, Lequier L, Vandermeer B, Tjosvold L, Larsen B, Hartling L, Cochrane Emergency and Critical Care Group. Nutritional support for critically ill children. Cochrane Database Syst Rev 2016; 2016:CD005144. [PMID: 27230550 PMCID: PMC6517095 DOI: 10.1002/14651858.cd005144.pub3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Nutritional support in the critically ill child has not been well investigated and is a controversial topic within paediatric intensive care. There are no clear guidelines as to the best form or timing of nutrition in critically ill infants and children. This is an update of a review that was originally published in 2009. . OBJECTIVES The objective of this review was to assess the impact of enteral and parenteral nutrition given in the first week of illness on clinically important outcomes in critically ill children. There were two primary hypotheses:1. the mortality rate of critically ill children fed enterally or parenterally is different to that of children who are given no nutrition;2. the mortality rate of critically ill children fed enterally is different to that of children fed parenterally.We planned to conduct subgroup analyses, pending available data, to examine whether the treatment effect was altered by:a. age (infants less than one year versus children greater than or equal to one year old);b. type of patient (medical, where purpose of admission to intensive care unit (ICU) is for medical illness (without surgical intervention immediately prior to admission), versus surgical, where purpose of admission to ICU is for postoperative care or care after trauma).We also proposed the following secondary hypotheses (a priori), pending other clinical trials becoming available, to examine nutrition more distinctly:3. the mortality rate is different in children who are given enteral nutrition alone versus enteral and parenteral combined;4. the mortality rate is different in children who are given both enteral feeds and parenteral nutrition versus no nutrition. SEARCH METHODS In this updated review we searched: the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 2); Ovid MEDLINE (1966 to February 2016); Ovid EMBASE (1988 to February 2016); OVID Evidence-Based Medicine Reviews; ISI Web of Science - Science Citation Index Expanded (1965 to February 2016); WebSPIRS Biological Abstracts (1969 to February 2016); and WebSPIRS CAB Abstracts (1972 to February 2016). We also searched trial registries, reviewed reference lists of all potentially relevant studies, handsearched relevant conference proceedings, and contacted experts in the area and manufacturers of enteral and parenteral nutrition products. We did not limit the search by language or publication status. SELECTION CRITERIA We included studies if they were randomized controlled trials; involved paediatric patients, aged one day to 18 years of age, who were cared for in a paediatric intensive care unit setting (PICU) and had received nutrition within the first seven days of admission; and reported data for at least one of the pre-specified outcomes (30-day or PICU mortality; length of stay in PICU or hospital; number of ventilator days; and morbid complications, such as nosocomial infections). We excluded studies if they only reported nutritional outcomes, quality of life assessments, or economic implications. Furthermore, we did not address other areas of paediatric nutrition, such as immunonutrition and different routes of delivering enteral nutrition, in this review. DATA COLLECTION AND ANALYSIS Two authors independently screened the searches, applied the inclusion criteria, and performed 'Risk of bias' assessments. We resolved discrepancies through discussion and consensus. One author extracted data and a second checked data for accuracy and completeness. We graded the evidence based on the following domains: study limitations, consistency of effect, imprecision, indirectness, and publication bias. MAIN RESULTS We identified only one trial as relevant. Seventy-seven children in intensive care with burns involving more than 25% of the total body surface area were randomized to either enteral nutrition within 24 hours or after at least 48 hours. No statistically significant differences were observed for mortality, sepsis, ventilator days, length of stay, unexpected adverse events, resting energy expenditure, nitrogen balance, or albumin levels. We assessed the trial as having unclear risk of bias. We consider the quality of the evidence to be very low due to there being only one small trial. In the most recent search update we identified a protocol for a relevant randomized controlled trial examining the impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients; no results have been published. AUTHORS' CONCLUSIONS There was only one randomized trial relevant to the review question. Research is urgently needed to identify best practices regarding the timing and forms of nutrition for critically ill infants and children.
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Affiliation(s)
- Ari Joffe
- University of Alberta and Stollery Children's HospitalDepartment of Pediatrics, Division of Pediatric Intensive CareOffice 3A3.078440‐ 112 StEdmontonABCanadaT6G 2B7
| | - Natalie Anton
- University of Alberta and Stollery Children's HospitalDepartment of Pediatrics, Division of Pediatric Intensive CareOffice 3A3.078440‐ 112 StEdmontonABCanadaT6G 2B7
| | - Laurance Lequier
- University of Alberta and Stollery Children's HospitalDepartment of Pediatrics, Division of Pediatric Intensive CareOffice 3A3.078440‐ 112 StEdmontonABCanadaT6G 2B7
| | - Ben Vandermeer
- University of AlbertaDepartment of Pediatrics and the Alberta Research Centre for Health Evidence11405 ‐ 87 AvenueEdmontonABCanadaT6G 1C9
| | - Lisa Tjosvold
- University of AlbertaAlberta Research Centre for Child Health EvidenceAberhart Centre One, Room 942011402 University Ave.EdmontonABCanadaT6G 2J3
| | - Bodil Larsen
- Stollery Children's HospitalNutrition ServiceEdmontonABCanadaT6G 2B7
| | - Lisa Hartling
- University of AlbertaDepartment of Pediatrics and the Alberta Research Centre for Health Evidence11405 ‐ 87 AvenueEdmontonABCanadaT6G 1C9
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Chang Z, Li Y, He W, Liu B, Halaweish I, Bambakidis T, Liang Y, Alam HB. Selective inhibition of histone deacetylase 6 promotes survival in a rat model of hemorrhagic shock. J Trauma Acute Care Surg 2016; 79:905-10. [PMID: 26680133 DOI: 10.1097/ta.0000000000000784] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Hemorrhage is the leading cause of preventable trauma-related deaths. We have previously shown that treatment with Tubastatin A (Tub A), a histone deacetylase 6 (HDAC6) inhibitor, can improve survival in a rodent model of septic shock. The aims of the present study were to determine whether selective inhibition of HDAC6 can promote survival in a model of hemorrhagic shock (HS). METHODS In Experiment I (survival study), Wistar-Kyoto rats were subjected to HS (55% volume blood loss), followed by intraperitoneal injection of either Tub A (70 mg/kg) dissolved in dimethyl sulfoxide (DMSO) or DMSO only (vehicle group) (n = 8 per group). Survival was monitored for 24 hours. In Experiment II (physiologic study), rats were subjected to a sublethal HS (40% blood loss), followed by the same treatment with Tub A (treatment group) or DMSO only (vehicle group, n = 5 per group). All animals were sacrificed 6 hours after hemorrhage, and the heart and liver tissues were harvested. Sham animals were not subjected to hemorrhage and treatment (sham group, n = 5 per group). Cardiac mitochondria were isolated to study the pyruvate dehydrogenase (PDH, an essential enzyme for adenosine triphosphate production) activity. Liver tissue lysates were analyzed for markers of apoptosis (cytochrome c, cleaved caspase 3) and inflammation (high-mobility group box 1) by Western blotting. RESULTS Severe HS (55% blood loss) was associated with 75% mortality, which was significantly improved by Tub A treatment (37.5% mortality in 24 hours, p = 0.048). Tub A also significantly enhanced the cardiac PDH activity compared with the vehicle group, while suppressing the hepatic high-mobility group box 1 expression, cytochrome c release, and caspase 3 activation. CONCLUSION Our study has demonstrated for the first time that selective inhibition of HDAC6 can improve survival in a rodent model of HS. The potential mechanisms include enhanced PDH activity, decreased inflammatory drive, and attenuated cellular apoptosis.
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Affiliation(s)
- Zhigang Chang
- From the Department of Surgical ICU (Z.C.), Beijing Hospital Ministry of Health, Beijing; Department of Cardiothoracic Surgery (W.H.), Zhongda Hospital, School of Medicine, Southeast University, Nanjing; and The First Hospital (Y.Lia.), China Medical University, Shengyang, China; and Department of Surgery (Z.C., Y.Li., W.H., B.L., I.H., T.B., Y.Lia., H.B.A.), University of Michigan Hospital, Ann Arbor, Michigan
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