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Laserna A, Cuenca JA, Martin P, Fowler C, Barahona-Correa J, Manjappachar N, Fowler C, Lopez-Olivo MA, Borges M, Sprung CL, Nates JL. Mortality time frame variability in septic shock clinical trials: A systematic review. Med Intensiva 2025:502172. [PMID: 40090798 DOI: 10.1016/j.medine.2025.502172] [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: 08/07/2024] [Revised: 01/31/2025] [Accepted: 02/06/2025] [Indexed: 03/18/2025]
Abstract
OBJECTIVE We sought to delineate the mortality outcome time frames reported in septic shock randomized control trials (RCTs). DESIGN Systematic review of PubMed, EMBASE, and the Cochrane Database of Systematic Reviews. SETTING Intensive care units. PARTICIPANTS Studies that included adult patients with septic shock. INTERVENTIONS Any type of intervention. MAIN VARIABLES OF INTEREST Information about the study, specific patient population, type of study intervention, specific intervention, and number of patients. Mortality time frames were analyzed for geographical differences and changes over time. RESULTS The search yielded 2660 unique citations. After screening, 132 eligible studies were identified. A total of 234 mortality time frames were collected from the included studies, of which 15 timeframes were unique. The most frequently reported time frame was 28-day mortality (n = 98, 74% of trials), followed by hospital mortality (n = 35, 27%), ICU mortality (n = 30, 23%), and 90-day mortality (n = 29, 22%). The most reported mortality time frame was 28 days in studies from every continent except Africa. The studies published between 2008 and 2013 (25%) more frequently reported hospital and ICU mortality combination than studies published between 2014 and 2019 (11.4%) (P = 0.043). CONCLUSIONS There was considerable variability in the mortality time frames reported in ICU-based septic shock trials. This variability may lead to under or overestimation of the problem, overlooking the effectiveness of the interventions studied, and further limiting the application of trials and their pooling in meta-analyses. A consensus regarding time frame reporting in septic shock trials is long overdue.
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Affiliation(s)
- Andres Laserna
- Department of Critical Care Medicine, Division of Anesthesiology, Critical Care, and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Stanford, California, United States
| | - John A Cuenca
- Department of Critical Care Medicine, Division of Anesthesiology, Critical Care, and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Texas Institute of Graduate Medical Education and Research (TIGMER), University of Incarnate Word, San Antonio, Texas, United States
| | - Peyton Martin
- Department of Critical Care Medicine, Division of Anesthesiology, Critical Care, and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Cosmo Fowler
- Department of Critical Care Medicine, Division of Anesthesiology, Critical Care, and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Julian Barahona-Correa
- Department of Internal Medicine, Hospital Universitario San Ignacio, Pontificia Universidad Javeriana, Bogota, Colombia
| | - Nirmala Manjappachar
- Department of Critical Care Medicine, Division of Anesthesiology, Critical Care, and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Clara Fowler
- Research Services and Assessment, Research Medical Library, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Maria A Lopez-Olivo
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Marcio Borges
- Multidisciplinary Sepsis Unit, ICU, Son Llàtzer University Hospital, Balearic, Palma de Mallorca, Spain
| | - Charles L Sprung
- Department of Anesthesiology, Critical Care Medicine and Pain Medicine, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Joseph L Nates
- Department of Critical Care Medicine, Division of Anesthesiology, Critical Care, and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
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Gziut T, Thanacoody R. L-carnitine for valproic acid-induced toxicity. Br J Clin Pharmacol 2025; 91:636-647. [PMID: 39261302 PMCID: PMC11862789 DOI: 10.1111/bcp.16233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/05/2024] [Accepted: 08/07/2024] [Indexed: 09/13/2024] Open
Abstract
AIMS Review the effectiveness and dosing of L-carnitine for valproic-acid induced toxicity. METHODS A literature review of the pharmacokinetics and clinical use of L-carnitine was performed. RESULTS Valproic acid is a fatty acid used for numerous therapeutic indications ranging from epilepsy to bipolar disorder. The metabolism of valproic acid produces both therapeutic and toxic metabolites. Whilst it has a good safety profile, adverse effects of valproic acid in chronic use include hepatotoxicity ranging from transient elevation of liver enzymes to fulminant liver failure and hyperammonaemia with resultant encephalopathy. L-carnitine is an essential cofactor for mitochondrial fatty acid metabolism, which is an important source of energy in cardiac and skeletal muscle. Physiological concentrations of L-carnitine are maintained in man by exogenous dietary intake and endogenous synthesis. Following exogenous oral administration of L-carnitine, the bioavailability ranges from 14% to 18%. After bolus intravenous administration of L-carnitine in doses ranging from 20 to 100 mg/kg, the volume of distribution is 0.2-0.3 L/kg, and the fraction excreted unchanged in urine is 0.73-0.95, suggesting that renal clearance of L-carnitine is dose dependent due to saturable renal reabsorption at supraphysiological concentrations. CONCLUSIONS There is evidence supporting the use of L-carnitine in treating hyperammonaemia and hepatotoxicity following chronic therapeutic use and after acute overdose of valproic acid, but the optimal dose and route of administration is unknown. Based on the pharmacokinetics of L-carnitine, we advocate the administration of L-carnitine for valproic-acid induced hyperammonaemia or hepatotoxicity as an intravenous loading dose of 5 mg/kg followed by a continuous intravenous infusion instead of the oral or intravenous boluses that are currently advocated.
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Affiliation(s)
- Tomasz Gziut
- National Poisons Information Service (Newcastle unit)Newcastle‐upon‐Tyne Hospitals NHS Foundation TrustUK
| | - Ruben Thanacoody
- National Poisons Information Service (Newcastle unit)Newcastle‐upon‐Tyne Hospitals NHS Foundation TrustUK
- Translational and Clinical Research InstituteNewcastle UniversityNewcastle‐upon‐TyneUK
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Ming S, Li X, Xiao Q, Qu S, Wang Q, Fang Q, Liang P, Xu Y, Yang J, Yang Y, Huang X, Wu Y. TREM2 aggravates sepsis by inhibiting fatty acid oxidation via the SHP1/BTK axis. J Clin Invest 2024; 135:e159400. [PMID: 39405126 DOI: 10.1172/jci159400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 10/08/2024] [Indexed: 01/03/2025] Open
Abstract
Impaired fatty acid oxidation (FAO) and the therapeutic benefits of FAO restoration have been revealed in sepsis. However, the regulatory factors contributing to FAO dysfunction during sepsis remain inadequately clarified. In this study, we identified a subset of lipid-associated macrophages characterized by high expression of trigger receptor expressed on myeloid cells 2 (TREM2) and demonstrated that TREM2 acted as a suppressor of FAO to increase the susceptibility to sepsis. TREM2 expression was markedly upregulated in sepsis patients and correlated with the severity of sepsis. Knockout of TREM2 in macrophages improved the survival rate and reduced inflammation and organ injuries of sepsis mice. Notably, TREM2-deficient mice exhibited decreased triglyceride accumulation and an enhanced FAO rate. Further observations showed that the blockade of FAO substantially abolished the alleviated symptoms observed in TREM2-knockout mice. Mechanically, we demonstrated that TREM2 interacted with the phosphatase SHP1 to inhibit bruton tyrosine kinase-mediated (BTK-mediated) FAO in sepsis. Our findings expand the understanding of FAO dysfunction in sepsis and reveal TREM2 as a critical regulator of FAO that may provide a promising target for the clinical treatment of sepsis.
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Affiliation(s)
- Siqi Ming
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Zhuhai Hospital, Zhuhai, China
| | - Xingyu Li
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Key Research Laboratory of Traditional Chinese Medicine in the Prevention and Treatment of Infectious Diseases, Traditional Chinese Medicine Bureau of Guangdong Province, the Fifth Affiliated Hospital, SunYat-Sen University, Zhuhai, China
| | - Qiang Xiao
- Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Siying Qu
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Qiaohua Wang
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Qiongyan Fang
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Pingping Liang
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Yating Xu
- National Clinical Research Center for Infectious Disease, Shenzhen Third People' s Hospital, the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Jingwen Yang
- Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Yongqiang Yang
- Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Zhuhai Hospital, Zhuhai, China
| | - Xi Huang
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Key Research Laboratory of Traditional Chinese Medicine in the Prevention and Treatment of Infectious Diseases, Traditional Chinese Medicine Bureau of Guangdong Province, the Fifth Affiliated Hospital, SunYat-Sen University, Zhuhai, China
- National Clinical Research Center for Infectious Disease, Shenzhen Third People' s Hospital, the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Yongjian Wu
- Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
- Key Research Laboratory of Traditional Chinese Medicine in the Prevention and Treatment of Infectious Diseases, Traditional Chinese Medicine Bureau of Guangdong Province, the Fifth Affiliated Hospital, SunYat-Sen University, Zhuhai, China
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Meng C, Ma Y, Fu N, Li J, Sun B, Li Z, Wang Q, Liu P. The supplementation of L-carnitine in critically ill patients with sepsis: a systematic review and meta-analysis of randomized controlled trials. Eur J Med Res 2024; 29:488. [PMID: 39367436 PMCID: PMC11453008 DOI: 10.1186/s40001-024-02087-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 09/28/2024] [Indexed: 10/06/2024] Open
Abstract
OBJECTIVES The evidence suggests that L-carnitine may reduce mortality in critically ill patients with sepsis. However, the conclusions of different studies are inconsistent. A meta-analysis was conducted to evaluate the effect of L-carnitine compliance on mortality in patients with sepsis. METHODS A search of the PubMed, Embase, and Cochrane Library databases was conducted on 1 June 2024. The risk ratio (RR) was pooled with a 95% confidence interval (CI) for dichotomous data. The publications were subjected to a review in accordance with the guidelines set forth in the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). This study has been registered with INPLASY (number INPLASY202460086). RESULTS A total of 356 patients were included in four randomized controlled trials. The results indicated that L-carnitine supplementation was not associated with 28-day mortality in sepsis patients (RR: 0.65; 95% CI 0.33-1.28; I2 = 70%; P = 0.21). And there was no significant effect on 12-month mortality (RR: 0.72; 95% CI 0.47-1.11; I2 = 0%; P = 0.14) compared to placebo. CONCLUSIONS The use of L-carnitine was not found to be significantly correlated with 28-day or 12-month mortality in patients with sepsis.
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Affiliation(s)
- Chang Meng
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, People's Republic of China
| | - Yudan Ma
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Fuxing Road 28, Haidian District, Beijing, 100039, People's Republic of China
| | - Ning Fu
- Department of Cardiology, Hebei Yanda Hospital, Langfang, 065201, People's Republic of China
| | - Jie Li
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, People's Republic of China
| | - Biao Sun
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, People's Republic of China
| | - Zhichao Li
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, People's Republic of China
| | - Qing Wang
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, People's Republic of China.
| | - Peng Liu
- Department of Cardiology, Ordos Central Hospital, Ordos School of Clinical Medicine, Inner Mongolia Medical University, 23 Yijin Huoluo West Street, Dongsheng District, Inner Mongolia, Ordos, 017000, People's Republic of China.
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Yagin FH, Aygun U, Algarni A, Colak C, Al-Hashem F, Ardigò LP. Platelet Metabolites as Candidate Biomarkers in Sepsis Diagnosis and Management Using the Proposed Explainable Artificial Intelligence Approach. J Clin Med 2024; 13:5002. [PMID: 39274215 PMCID: PMC11395774 DOI: 10.3390/jcm13175002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 08/16/2024] [Accepted: 08/22/2024] [Indexed: 09/16/2024] Open
Abstract
Background: Sepsis is characterized by an atypical immune response to infection and is a dangerous health problem leading to significant mortality. Current diagnostic methods exhibit insufficient sensitivity and specificity and require the discovery of precise biomarkers for the early diagnosis and treatment of sepsis. Platelets, known for their hemostatic abilities, also play an important role in immunological responses. This study aims to develop a model integrating machine learning and explainable artificial intelligence (XAI) to identify novel platelet metabolomics markers of sepsis. Methods: A total of 39 participants, 25 diagnosed with sepsis and 14 control subjects, were included in the study. The profiles of platelet metabolites were analyzed using quantitative 1H-nuclear magnetic resonance (NMR) technology. Data were processed using the synthetic minority oversampling method (SMOTE)-Tomek to address the issue of class imbalance. In addition, missing data were filled using a technique based on random forests. Three machine learning models, namely extreme gradient boosting (XGBoost), light gradient boosting machine (LightGBM), and kernel tree boosting (KTBoost), were used for sepsis prediction. The models were validated using cross-validation. Clinical annotations of the optimal sepsis prediction model were analyzed using SHapley Additive exPlanations (SHAP), an XAI technique. Results: The results showed that the KTBoost model (0.900 accuracy and 0.943 AUC) achieved better performance than the other models in sepsis diagnosis. SHAP results revealed that metabolites such as carnitine, glutamate, and myo-inositol are important biomarkers in sepsis prediction and intuitively explained the prediction decisions of the model. Conclusion: Platelet metabolites identified by the KTBoost model and XAI have significant potential for the early diagnosis and monitoring of sepsis and improving patient outcomes.
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Affiliation(s)
- Fatma Hilal Yagin
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, Malatya 44280, Türkiye
| | - Umran Aygun
- Department of Anesthesiology and Reanimation, Malatya Yesilyurt Hasan Calık State Hospital, Malatya 44929, Türkiye
| | - Abdulmohsen Algarni
- Central Labs, King Khalid University, AlQura'a, Abha, P.O. Box 960, Saudi Arabia
| | - Cemil Colak
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, Malatya 44280, Türkiye
| | - Fahaid Al-Hashem
- Department of Physiology, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia
| | - Luca Paolo Ardigò
- Department of Teacher Education, NLA University College, 0166 Oslo, Norway
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Safabakhsh M, Imani H, Shahinfar H, Mohammadpour M, Rohani P, Shab-Bidar S. Efficacy of dietary supplements on mortality and clinical outcomes in adults with sepsis and septic shock: A systematic review and network meta-analysis. Clin Nutr 2024; 43:1299-1307. [PMID: 38663051 DOI: 10.1016/j.clnu.2024.03.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/19/2024] [Accepted: 03/29/2024] [Indexed: 05/31/2024]
Abstract
AIM The aim of this network meta-analysis (NMA) was to investigate the effects of different dietary supplements on the mortality and clinical status of adults with sepsis. METHODS We searched PubMed, EMBASE, and the Cochrane Library Central Register of Controlled Trials until February 2023. The inclusion criteria were: 1) randomized controlled trials (RCT)s; 2) adults suffering sepsis or septic shock; 3) evaluation of short- or long-mortality; and 4) publications between 1994 and 2023. The general information of studies and details of interventions were extracted. The primary outcome was short-term mortality (<90 days), and the secondary outcomes were long-term mortality (≥90 days), length of ICU and hospital stays, and duration of mechanical ventilation (MV). The risk of bias of RCTs was assessed using the Cochrane risk of bias tool 2 (ROB2). A random effect NMA was performed to rank the effect of each intervention using a frequentist approach. RESULTS Finally, 56 RCTs with 5957 participants met the criteria. Approximately, one-third of RCTs were low risk of bias. NMA analysis revealed that there was no treatment more effective in short- or long-term mortality than control or other interventions, except for magnesium (RR: 0.33, 95% CI: 0.14, 0.79; GRADE = low) and vitamin C (RR: 0.81, 95% CI: 0.67, 0.99; low certainty evidence), which had beneficial effects on short-term mortality. Moreover, eicosapentaenoic acid, gamma-linolenic acid, and antioxidants (EPA + GLA + AOs) combination was the most effective, and magnesium, vitamin D and vitamin C were the other effective approaches in terms of duration of MV, and ICU length of stay. There was no beneficial dietary supplement for hospital stay in these patients. CONCLUSIONS In septic patients, none of the dietary supplements had a substantial effect on mortality except for magnesium and vitamin C, which were linked to lower short-term mortality with low certainty of evidence. Further investigation into high-quality studies with the use of dietary supplements for sepsis should be highly discouraged.
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Affiliation(s)
- Maryam Safabakhsh
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Hossein Imani
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Hossein Shahinfar
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Masoud Mohammadpour
- Division of Pediatric Intensive Care Unit, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Pejman Rohani
- Pediatric Gastroenterology, Hepatology and Nutrition Research Center, Research Institute for Children Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sakineh Shab-Bidar
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran; Sports Medicine Research Center, Neuroscience Institute, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
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Keshani M, Alikiaii B, Babaei Z, Askari G, Heidari Z, Sharma M, Bagherniya M. The effects of L-carnitine supplementation on inflammation, oxidative stress, and clinical outcomes in critically Ill patients with sepsis: a randomized, double-blind, controlled trial. Nutr J 2024; 23:31. [PMID: 38444016 PMCID: PMC10916166 DOI: 10.1186/s12937-024-00934-4] [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: 12/09/2023] [Accepted: 02/28/2024] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND Sepsis, a life-threatening organ dysfunction caused by a host's dysregulated response to infection with an inflammatory process, becomes a real challenge for the healthcare systems. L-carnitine (LC) has antioxidant and anti-inflammatory properties as in previous studies. Thus, we aimed to determine the effects of LC on inflammation, oxidative stress, and clinical parameters in critically ill septic patients. METHODS A randomized double-blinded controlled trial was conducted. A total of 60 patients were randomized to receive LC (3 g/day, n = 30) or placebo (n = 30) for 7 days. Inflammatory and oxidative stress parameters (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), superoxide dismutase (SOD), malondialdehyde (MDA), total antioxidant capacity (TAC), 28-day mortality rate, and some monitoring variables were evaluated. RESULTS There was no statistically significant difference between study arms in baseline characteristics and disease severity scores. CRP (p < 0.001) and ESR (p: 0.004) significantly reduced, and SOD (p < 0.001) and TAC (p < 0.001) significantly improved in the LC group after 7 days. Between-group analysis revealed a significant reduction in CRP (p: 0.001) and serum chloride (p: 0.032), an increase in serum albumin (p: 0.036) and platelet (p: 0.004) significantly, and an increase in SOD marginally (p: 0.073). The 28-day mortality rate was also lower in the LC group compared with placebo (7 persons vs. 15 persons) significantly (odds ratio: 0.233, p: 0.010). CONCLUSIONS L-carnitine ameliorated inflammation, enhanced antioxidant defense, reduced mortality, and improved some clinical outcomes in critically ill patients with sepsis. TRIAL REGISTRATION IRCT20201129049534N1; May 2021.
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Affiliation(s)
- Mahdi Keshani
- Nutrition and Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Babak Alikiaii
- Anesthesia and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Babaei
- Department of Nursing and Midwifery, Islamic Azad University Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Gholamreza Askari
- Nutrition and Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
- Anesthesia and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Heidari
- Department of Biostatistics and Epidemiology, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Manoj Sharma
- Department of Social & Behavioral Health, School of Public Health, & Department of Internal Medicine, University of Nevada, Las Vegas, USA
| | - Mohammad Bagherniya
- Nutrition and Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
- Anesthesia and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
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Oi M, Maruhashi T, Asari Y. Carnitine Deficiency in Intensive Care Unit Patients Undergoing Continuous Renal Replacement Therapy: A Single-center Retrospective Study. JMA J 2024; 7:70-76. [PMID: 38314424 PMCID: PMC10834172 DOI: 10.31662/jmaj.2023-0112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 09/29/2023] [Indexed: 02/06/2024] Open
Abstract
Introduction Carnitine deficiency is common in patients undergoing intermittent hemodialysis and may also occur during continuous renal replacement therapy (CRRT). We evaluated intensive care unit (ICU) patients undergoing CRRT for carnitine deficiency and its associated risk factors. Methods This was a single-center, retrospective, observational study performed between June 2019 and March 2020. The primary outcome was the incidence of carnitine deficiency in ICU patients undergoing CRRT. Results Eighty-eight patients underwent 103 blood carnitine concentration measurements. The median age was 68 years (interquartile range: 55-80), Acute Physiology and Chronic Health Evaluation II score was 28 (24-33), Sequential Organ Failure score was 8.5 (5-11), Nutrition Risk in Critically Ill score was 6 (5-7), and blood carnitine concentration was 66.1 μmol/L (51.8-83.3). In total, 34 of 88 patients (38.6%) were found to have carnitine deficiency; however, there was no significant difference in the proportions of patients with carnitine deficiency characterized by disease. CRRT was performed in 44 (50%) patients, and the median blood total carnitine concentration measured after 24 h of CRRT without changing the settings was 65.5 μmol/L (48.6-83.3). The purification volume of CRRT and blood carnitine concentration were negatively correlated (R = -0.63; P = 0.02). Conclusions Carnitine deficiency is seen in patients receiving CRRT and may increase in incidence as the purification volume increases, requiring regular monitoring.
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Affiliation(s)
- Marina Oi
- Department of Emergency and Critical Care Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takaaki Maruhashi
- Department of Emergency and Critical Care Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yasushi Asari
- Department of Emergency and Critical Care Medicine, Kitasato University School of Medicine, Sagamihara, Japan
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Abdalla W, Ammar MA, Ali A, Ragab D, Taeimah M. Effects of high-dose L-carnitine supplementation on diaphragmatic function in patients with respiratory failure: A randomized clinical trial. EGYPTIAN JOURNAL OF ANAESTHESIA 2023. [DOI: 10.1080/11101849.2023.2168852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Affiliation(s)
- Waleed Abdalla
- Department of Anesthesia, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mona A. Ammar
- Department of Anesthesia, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Asmaa Ali
- Department of Pulmonary Medicine, Abbassia Chest Hospital, MOH, Cairo, Egypt
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jingkou, China
| | - Dina Ragab
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed Taeimah
- Department of Anesthesia, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Jennaro TS, Puskarich MA, Flott TL, McLellan LA, Jones AE, Pai MP, Stringer KA. Kidney function as a key driver of the pharmacokinetic response to high-dose L-carnitine in septic shock. Pharmacotherapy 2023; 43:1240-1250. [PMID: 37775945 PMCID: PMC10841498 DOI: 10.1002/phar.2882] [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: 05/12/2023] [Revised: 08/22/2023] [Accepted: 08/31/2023] [Indexed: 10/01/2023]
Abstract
STUDY OBJECTIVE Levocarnitine (L-carnitine) has shown promise as a metabolic-therapeutic for septic shock, where mortality approaches 40%. However, high-dose (≥ 6 grams) intravenous supplementation results in a broad range of serum concentrations. We sought to describe the population pharmacokinetics (PK) of high-dose L-carnitine, test various estimates of kidney function, and assess the correlation of PK parameters with pre-treatment metabolites in describing drug response for patients with septic shock. DESIGN Population PK analysis was done with baseline normalized concentrations using nonlinear mixed effect models in the modeling platform Monolix. Various estimates of kidney function, patient demographics, dose received, and organ dysfunction were tested as population covariates. DATA SOURCE We leveraged serum samples and metabolomics data from a phase II trial of L-carnitine in vasopressor-dependent septic shock. Serum was collected at baseline (T0); end-of-infusion (T12); and 24, 48, and 72 h after treatment initiation. PATIENTS AND INTERVENTION Patients were adaptively randomized to receive intravenous L-carnitine (6 grams, 12 grams, or 18 grams) or placebo. MEASUREMENTS AND MAIN RESULTS The final dataset included 542 serum samples from 130 patients randomized to L-carnitine. A two-compartment model with linear elimination and a fixed volume of distribution (17.1 liters) best described the data and served as a base structural model. Kidney function estimates as a covariate on the elimination rate constant (k) reliably improved model fit. Estimated glomerular filtration rate (eGFR), based on the 2021 Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation with creatinine and cystatin C, outperformed creatinine clearance (Cockcroft-Gault) and older CKD-EPI equations that use an adjustment for self-identified race. CONCLUSIONS High-dose L-carnitine supplementation is well-described by a two-compartment population PK model in patients with septic shock. Kidney function estimates that leverage cystatin C provided superior model fit. Future investigations into high-dose L-carnitine supplementation should consider baseline metabolic status and dose adjustments based on renal function over a fixed or weight-based dosing paradigm.
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Affiliation(s)
- Theodore S. Jennaro
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Michael A. Puskarich
- Department of Emergency Medicine, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA
| | - Thomas L. Flott
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Laura A. McLellan
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Alan E. Jones
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Manjunath P. Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Kathleen A. Stringer
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
- The Max Harry Weil Institute for Critical Care Research and Innovation, University of Michigan, Ann Arbor, Michigan, USA
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA
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11
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Lauwers C, De Bruyn L, Langouche L. Impact of critical illness on cholesterol and fatty acids: insights into pathophysiology and therapeutic targets. Intensive Care Med Exp 2023; 11:84. [PMID: 38015312 PMCID: PMC10684846 DOI: 10.1186/s40635-023-00570-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 11/21/2023] [Indexed: 11/29/2023] Open
Abstract
Critical illness is characterized by a hypercatabolic response encompassing endocrine and metabolic alterations. Not only the uptake, synthesis and metabolism of glucose and amino acids is majorly affected, but also the homeostasis of lipids and cholesterol is altered during acute and prolonged critical illness. Patients who suffer from critically ill conditions such as sepsis, major trauma, surgery or burn wounds display an immediate and sustained reduction in low plasma LDL-, HDL- and total cholesterol concentrations, together with a, less pronounced, increase in plasma free fatty acids. The severity of these alterations is associated with severity of illness, but the underlying pathophysiological mechanisms are multifactorial and only partly clarified. This narrative review aims to provide an overview of the current knowledge of how lipid and cholesterol uptake, synthesis and metabolism is affected during critical illness. Reduced nutritional uptake, increased scavenging of lipoproteins as well as an increased conversion to cortisol or other cholesterol-derived metabolites might all play a role in the decrease in plasma cholesterol. The acute stress response to critical illness creates a lipolytic cocktail, which might explain the increase in plasma free fatty acids, although reduced uptake and oxidation, but also increased lipogenesis, especially in prolonged critical illness, will also affect the circulating levels. Whether a disturbed lipid homeostasis warrants intervention or should primarily be interpreted as a signal of severity of illness requires further research.
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Affiliation(s)
- Caroline Lauwers
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, O&N1 Box 503, 3000, Leuven, Belgium
| | - Lauren De Bruyn
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, O&N1 Box 503, 3000, Leuven, Belgium
| | - Lies Langouche
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, O&N1 Box 503, 3000, Leuven, Belgium.
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12
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Arabi SM, Hadi S, Gholambareshi P, Bahrami LS, Hazrati E, Mirghazanfari SM, Sahebkar A, Hadi V. The effect of l-carnitine supplementation on mortality and clinical outcomes in ventilator-dependent critically ill patients with obesity and COVID-19: Protocol for a randomized double-blind placebo-controlled trial. Contemp Clin Trials Commun 2023; 32:101082. [PMID: 36742110 PMCID: PMC9886566 DOI: 10.1016/j.conctc.2023.101082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 01/01/2023] [Accepted: 01/28/2023] [Indexed: 02/02/2023] Open
Abstract
Background Coronavirus disease 2019 (COVID-19) still remains a pandemic accounting for at least 15% of intensive care unit (ICU) admissions. Recently, it has been observed that l-carnitine levels, which play an important role in fatty acid metabolism, have an inverse association with the severity of COVID-19 and its complications, hence a potential role for supplementing with this nutraceutical has been suggested. The current protocol describes a trial aiming to an evaluation of the effect of l-carnitine intervention on mortality and clinical outcomes in ICU-admitted patients with COVID-19. Methods This parallel-group, randomized, placebo-controlled, and double-blind clinical trial involves 50 participants and will be performed at the ICU of Artesh (AJA) Hospital, Mashhad, IRAN. Eligible participants will be randomized into two groups: 1) the intervention group will receive 1000 mg l-carnitine capsules 3 times a day, and 2) the placebo group will receive 1000 mg placebo capsules 3 times a day. Assessments will be performed at baseline, 7 and 28 days after study initiation. The primary outcome includes changes in serum levels of C-reactive protein (CRP). Secondary outcomes include the length of stay in the ICU, ICU mortality, hospital mortality, 28-day mortality, duration of mechanical ventilation (MV), and the neutrophil-lymphocyte ratio (NLR). Conclusion Based on previous evidence, l-carnitine may reduce inflammation and oxidation stress and improve respiratory function. However, the effects of l-carnitine on ventilator-dependent COVID-19 critically ill patients have not been assessed yet, justifying the necessity to conduct a clinical study in this field. c.
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Affiliation(s)
- Seyyed Mostafa Arabi
- Department of Biochemistry and Nutrition, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran.,Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Saeid Hadi
- Department of Health, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Parisa Gholambareshi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Leila Sadat Bahrami
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.,Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ebrahim Hazrati
- Trauma Research Center, AJA University of Medical Sciences, Tehran, Iran
| | - Sayid Mahdi Mirghazanfari
- Department of Physiology and Iranian Medicine, School of Medicine, AJA University of Medical Sciences, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahid Hadi
- Department of Biochemistry and Nutrition, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
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13
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Berger MM, Shenkin A, Schweinlin A, Amrein K, Augsburger M, Biesalski HK, Bischoff SC, Casaer MP, Gundogan K, Lepp HL, de Man AME, Muscogiuri G, Pietka M, Pironi L, Rezzi S, Cuerda C. ESPEN micronutrient guideline. Clin Nutr 2022; 41:1357-1424. [PMID: 35365361 DOI: 10.1016/j.clnu.2022.02.015] [Citation(s) in RCA: 266] [Impact Index Per Article: 88.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 02/16/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Trace elements and vitamins, named together micronutrients (MNs), are essential for human metabolism. Recent research has shown the importance of MNs in common pathologies, with significant deficiencies impacting the outcome. OBJECTIVE This guideline aims to provide information for daily clinical nutrition practice regarding assessment of MN status, monitoring, and prescription. It proposes a consensus terminology, since many words are used imprecisely, resulting in confusion. This is particularly true for the words "deficiency", "repletion", "complement", and "supplement". METHODS The expert group attempted to apply the 2015 standard operating procedures (SOP) for ESPEN which focuses on disease. However, this approach could not be applied due to the multiple diseases requiring clinical nutrition resulting in one text for each MN, rather than for diseases. An extensive search of the literature was conducted in the databases Medline, PubMed, Cochrane, Google Scholar, and CINAHL. The search focused on physiological data, historical evidence (published before PubMed release in 1996), and observational and/or randomized trials. For each MN, the main functions, optimal analytical methods, impact of inflammation, potential toxicity, and provision during enteral or parenteral nutrition were addressed. The SOP wording was applied for strength of recommendations. RESULTS There was a limited number of interventional trials, preventing meta-analysis and leading to a low level of evidence. The recommendations underwent a consensus process, which resulted in a percentage of agreement (%): strong consensus required of >90% of votes. Altogether the guideline proposes sets of recommendations for 26 MNs, resulting in 170 single recommendations. Critical MNs were identified with deficiencies being present in numerous acute and chronic diseases. Monitoring and management strategies are proposed. CONCLUSION This guideline should enable addressing suboptimal and deficient status of a bundle of MNs in at-risk diseases. In particular, it offers practical advice on MN provision and monitoring during nutritional support.
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Affiliation(s)
- Mette M Berger
- Department of Adult Intensive Care, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
| | - Alan Shenkin
- Institute of Aging and Chronic Disease, University of Liverpool, Liverpool, UK.
| | - Anna Schweinlin
- Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
| | - Karin Amrein
- Medical University of Graz, Department of Internal Medicine, Division of Endocrinology and Diabetology, Austria.
| | - Marc Augsburger
- University Centre of Legal Medicine Lausanne-Geneva, Lausanne University Hospital and University of Lausanne, Geneva University Hospital and University of Geneva, Lausanne-Geneva, Switzerland.
| | | | - Stephan C Bischoff
- Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.
| | - Michael P Casaer
- KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Intensive Care Medicine, Leuven, Belgium.
| | - Kursat Gundogan
- Division of Intensive Care Medicine, Department of Internal Medicine, Erciyes University School of Medicine, Kayseri, Turkey.
| | | | - Angélique M E de Man
- Department of Intensive Care Medicine, Research VUmc Intensive Care (REVIVE), Amsterdam Cardiovascular Science (ACS), Amsterdam Infection and Immunity Institute (AI&II), Amsterdam Medical Data Science (AMDS), Amsterdam UMC, Location VUmc, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
| | - Giovanna Muscogiuri
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università di Napoli (Federico II), Naples, Italy; United Nations Educational, Scientific and Cultural Organization (UNESCO) Chair for Health Education and Sustainable Development, Federico II, University, Naples, Italy.
| | - Magdalena Pietka
- Pharmacy Department, Stanley Dudrick's Memorial Hospital, Skawina, Poland.
| | - Loris Pironi
- Alma Mater Studiorum - University of Bologna, Department of Medical and Surgical Sciences, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Centre for Chronic Intestinal Failure - Clinical Nutrition and Metabolism Unit, Italy.
| | - Serge Rezzi
- Swiss Nutrition and Health Foundation (SNHf), Epalinges, Switzerland.
| | - Cristina Cuerda
- Departamento de Medicina, Universidad Complutense de Madrid, Nutrition Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
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14
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Hussain H, Vutipongsatorn K, Jiménez B, Antcliffe DB. Patient Stratification in Sepsis: Using Metabolomics to Detect Clinical Phenotypes, Sub-Phenotypes and Therapeutic Response. Metabolites 2022; 12:metabo12050376. [PMID: 35629881 PMCID: PMC9145582 DOI: 10.3390/metabo12050376] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/01/2022] [Accepted: 04/12/2022] [Indexed: 11/16/2022] Open
Abstract
Infections are common and need minimal treatment; however, occasionally, due to inappropriate immune response, they can develop into a life-threatening condition known as sepsis. Sepsis is a global concern with high morbidity and mortality. There has been little advancement in the treatment of sepsis, outside of antibiotics and supportive measures. Some of the difficulty in identifying novel therapies is the heterogeneity of the condition. Metabolic phenotyping has great potential for gaining understanding of this heterogeneity and how the metabolic fingerprints of patients with sepsis differ based on survival, organ dysfunction, disease severity, type of infection, treatment or causative organism. Moreover, metabolomics offers potential for patient stratification as metabolic profiles obtained from analytical platforms can reflect human individuality and phenotypic variation. This article reviews the most relevant metabolomic studies in sepsis and aims to provide an overview of the metabolic derangements in sepsis and how metabolic phenotyping has been used to identify sub-groups of patients with this condition. Finally, we consider the new avenues that metabolomics could open, exploring novel phenotypes and untangling the heterogeneity of sepsis, by looking at advances made in the field with other -omics technologies.
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Affiliation(s)
- Humma Hussain
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK; (H.H.); (K.V.)
| | - Kritchai Vutipongsatorn
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK; (H.H.); (K.V.)
| | - Beatriz Jiménez
- Section of Bioanalytical Chemistry, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK;
- National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
| | - David B. Antcliffe
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK; (H.H.); (K.V.)
- Correspondence:
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15
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Yahyapoor F, Sedaghat A, feizi A, Bagherniya M, Pahlavani N, Khadem-Rezaiyan M, Safarian M, Islam MS, Zarifi SH, Arabi M, Norouzy A. The effects of L-Carnitine supplementation on inflammatory markers, clinical status, and 28 days mortality in critically ill patients: A double-blind, randomized, placebo-controlled trial. Clin Nutr ESPEN 2022; 49:61-67. [DOI: 10.1016/j.clnesp.2022.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/13/2022] [Accepted: 04/01/2022] [Indexed: 11/30/2022]
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16
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Guedes GV, Minicucci MF, Tanni SE. The supplementation of L-carnitine in septic shock patients: Systematic review and meta-analysis. Clinics (Sao Paulo) 2022; 77:100124. [PMID: 36327640 PMCID: PMC9636543 DOI: 10.1016/j.clinsp.2022.100124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 09/30/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Sepsis and septic shock are severe and difficult-to-treat conditions with high lethality. There is interest in identifying new adjunct therapies that are effective in reducing mortality. In this context, L-carnitine has been investigated in trials as a potentially beneficial drug. Therefore, the aim of this systematic review was to assess the clinical evidence to support the use of L-carnitine in septic shock patients to reduce the risk of mortality. The objective of this review was to evaluate the effect of L-carnitine compared to placebo or Usual Care (UC) on the mortality rate in hospitalized adult septic shock patients. METHODS The authors exclusively included randomized clinical trials that compared the use of L-carnitine versus placebo in adult (> 18 years old) septic shock patients. The outcome was a mortality rate of 28 days. This systematic review and meta-analysis were performed following the PRISMA guidelines and registered in PROSPERO with the ID CRD42020180499. RESULTS Following the initial search, 4007 citations were identified, with 2701 remaining after duplicate removal. Eight citations were selected for body text reading, and two were selected for inclusion. The studies enrolled 275 patients, with 186 in the carnitine arm and 89 in the placebo arm. The effect of L-carnitine uses in septic shock patients showed a difference risk of -0.03 (95% Confidence Interval: -0.15-0.10, I2 = 77%, p = 0.69) compared to placebo/in mortality rate with low quality of evidence. CONCLUSIONS There is low-quality evidence that the use of L-carnitine has no significant effect on reducing 28-day mortality in septic shock patients.
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Affiliation(s)
- Gabriel Voltani Guedes
- Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil.
| | - Marcos Ferreira Minicucci
- Internal Medicine Department, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil
| | - Suzana Erico Tanni
- Internal Medicine Department, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil
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17
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Sahebnasagh A, Avan R, Monajati M, Hashemi J, Habtemariam S, Negintaji S, Saghafi F. L-carnitine: Searching for New Therapeutic Strategy for Sepsis Management. Curr Med Chem 2021; 29:3300-3323. [PMID: 34789120 DOI: 10.2174/0929867328666211117092345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 08/19/2021] [Accepted: 08/21/2021] [Indexed: 11/22/2022]
Abstract
In this review, we discussed the biological targets of carnitine, its effects on immune function, and how L-carnitine supplementation may help critically ill patients. L-carnitine is a potent antioxidant. L-carnitine depletion has been observed in prolonged intensive care unit (ICU) stays, while L-carnitine supplementation has beneficial effects in health promotion and regulation of immunity. It is essential for the uptake of fatty acids into mitochondria. By inhibiting the ubiquitin-proteasome system, down-regulation of apelin receptor in cardiac tissue, and reducing β-oxidation of fatty acid, carnitine may decrease vasopressor requirement in septic shock and improve clinical outcomes of this group of patients. We also have an overview of animal and clinical studies that have been recruited for evaluating the beneficial effects of L-carnitine in the management of sepsis/ septic shock. Additional clinical data are required to evaluate the optimal daily dose and duration of L-carnitine supplementation.
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Affiliation(s)
- Adeleh Sahebnasagh
- Clinical Research Center, Department of Internal Medicine, North Khorasan University of Medical Sciences, Bojnurd. Iran
| | - Razieh Avan
- Department of Clinical Pharmacy, Medical Toxicology and Drug Abuse Research Center (MTDRC), Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand. Iran
| | - Mahila Monajati
- Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan. Iran
| | - Javad Hashemi
- Department of Pathobiology and Laboratory Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd. Iran
| | - Solomon Habtemariam
- Pharmacognosy Research Laboratories and Herbal Analysis Services, School of Science, University of Greenwich, Central Avenue, Chatham-Maritime, Kent ME4 4TB. United Kingdom
| | - Sina Negintaji
- Student Research Committee, School of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd. Iran
| | - Fatemeh Saghafi
- Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd. Iran
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18
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Puskarich MA, Jennaro TS, Gillies CE, Evans CR, Karnovsky A, McHugh CE, Flott TL, Jones AE, Stringer KA. Pharmacometabolomics identifies candidate predictor metabolites of an L-carnitine treatment mortality benefit in septic shock. Clin Transl Sci 2021; 14:2288-2299. [PMID: 34216108 PMCID: PMC8604225 DOI: 10.1111/cts.13088] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/22/2021] [Accepted: 05/12/2021] [Indexed: 01/08/2023] Open
Abstract
Sepsis‐induced metabolic dysfunction contributes to organ failure and death. L‐carnitine has shown promise for septic shock, but a recent phase II study of patients with vasopressor‐dependent septic shock demonstrated a non‐significant reduction in mortality. We undertook a pharmacometabolomics study of these patients (n = 250) to identify metabolic profiles predictive of a 90‐day mortality benefit from L‐carnitine. The independent predictive value of each pretreatment metabolite concentration, adjusted for L‐carnitine dose, on 90‐day mortality was determined by logistic regression. A grid‐search analysis maximizing the Z‐statistic from a binomial proportion test identified specific metabolite threshold levels that discriminated L‐carnitine responsive patients. Threshold concentrations were further assessed by hazard ratio and Kaplan‐Meier estimate. Accounting for L‐carnitine treatment and dose, 11 1H‐NMR metabolites and 12 acylcarnitines were independent predictors of 90‐day mortality. Based on the grid‐search analysis numerous acylcarnitines and valine were identified as candidate metabolites of drug response. Acetylcarnitine emerged as highly viable for the prediction of an L‐carnitine mortality benefit due to its abundance and biological relevance. Using its most statistically significant threshold concentration, patients with pretreatment acetylcarnitine greater than or equal to 35 µM were less likely to die at 90 days if treated with L‐carnitine (18 g) versus placebo (p = 0.01 by log rank test). Metabolomics also identified independent predictors of 90‐day sepsis mortality. Our proof‐of‐concept approach shows how pharmacometabolomics could be useful for tackling the heterogeneity of sepsis and informing clinical trial design. In addition, metabolomics can help understand mechanisms of sepsis heterogeneity and variable drug response, because sepsis induces alterations in numerous metabolite concentrations.
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Affiliation(s)
- Michael A Puskarich
- Department of Emergency Medicine, University of Minnesota, Minneapolis, Minnesota, USA.,Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA
| | - Theodore S Jennaro
- The NMR Metabolomics Laboratory and the Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Christopher E Gillies
- Department of Emergency Medicine, University of Michigan, Ann Arbor, Michigan, USA.,Michigan Center for Integrative Research in Critical Care (MCIRCC), University of Michigan, Ann Arbor, Michigan, USA.,Michigan Institute for Data Science, Office of Research, University of Michigan, Ann Arbor, Michigan, USA
| | - Charles R Evans
- Michigan Regional Comprehensive Metabolomics Resource Core (MRC2, ), University of Michigan, Ann Arbor, Michigan, USA.,Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Alla Karnovsky
- Michigan Regional Comprehensive Metabolomics Resource Core (MRC2, ), University of Michigan, Ann Arbor, Michigan, USA.,Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
| | - Cora E McHugh
- The NMR Metabolomics Laboratory and the Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Thomas L Flott
- The NMR Metabolomics Laboratory and the Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Alan E Jones
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Kathleen A Stringer
- The NMR Metabolomics Laboratory and the Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.,Michigan Center for Integrative Research in Critical Care (MCIRCC), University of Michigan, Ann Arbor, Michigan, USA.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA
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19
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Pagano G, Manfredi C, Pallardó FV, Lyakhovich A, Tiano L, Trifuoggi M. Potential roles of mitochondrial cofactors in the adjuvant mitigation of proinflammatory acute infections, as in the case of sepsis and COVID-19 pneumonia. Inflamm Res 2021; 70:159-170. [PMID: 33346851 PMCID: PMC7750159 DOI: 10.1007/s00011-020-01423-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/29/2020] [Accepted: 11/11/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND The mitochondrial cofactors α-lipoic acid (ALA), coenzyme Q10 (CoQ10) and carnitine (CARN) play distinct and complementary roles in mitochondrial functioning, along with strong antioxidant actions. Also termed mitochondrial nutrients (MNs), these cofactors have demonstrated specific protective actions in a number of chronic disorders, as assessed in a well-established body of literature. METHODS Using PubMed, the authors searched for articles containing information on the utilization of MNs in inflammatory disorders as assessed from in vitro and animal studies, and in clinical trials, in terms of exerting anti-inflammatory actions. RESULTS The retrieved literature provided evidence relating acute pathologic conditions, such as sepsis and pneumonia, with a number of redox endpoints of biological and clinical relevance. Among these findings, both ALA and CARN were effective in counteracting inflammation-associated redox biomarkers, while CoQ10 showed decreased levels in proinflammatory conditions. MN-associated antioxidant actions were applied in a number of acute disorders, mostly using one MN. The body of literature assessing the safety and the complementary roles of MNs taken together suggests an adjuvant role of MN combinations in counteracting oxidative stress in sepsis and other acute disorders, including COVID-19-associated pneumonia. CONCLUSIONS The present state of art in the use of individual MNs in acute disorders suggests planning adjuvant therapy trials utilizing MN combinations aimed at counteracting proinflammatory conditions, as in the case of pneumonia and the COVID-19 pandemic.
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Affiliation(s)
- Giovanni Pagano
- Department of Chemical Sciences, Federico II Naples University, Via Cintia, 80126, Naples, Italy.
| | - Carla Manfredi
- Department of Chemical Sciences, Federico II Naples University, Via Cintia, 80126, Naples, Italy
| | - Federico V Pallardó
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia-INCLIVA, CIBERER, 46010, Valencia, Spain
| | - Alex Lyakhovich
- Vall d'Hebron Institut de Recerca, 08035, Barcelona, Spain
- Institute of Molecular Biology and Biophysics of the "Federal Research Center of Fundamental and Translational Medicine", 630117, Novosibirsk, Russia
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnical University of Marche, 60100, Ancona, Italy
| | - Marco Trifuoggi
- Department of Chemical Sciences, Federico II Naples University, Via Cintia, 80126, Naples, Italy
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20
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McCann MR, George De la Rosa MV, Rosania GR, Stringer KA. L-Carnitine and Acylcarnitines: Mitochondrial Biomarkers for Precision Medicine. Metabolites 2021; 11:51. [PMID: 33466750 PMCID: PMC7829830 DOI: 10.3390/metabo11010051] [Citation(s) in RCA: 168] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 12/11/2022] Open
Abstract
Biomarker discovery and implementation are at the forefront of the precision medicine movement. Modern advances in the field of metabolomics afford the opportunity to readily identify new metabolite biomarkers across a wide array of disciplines. Many of the metabolites are derived from or directly reflective of mitochondrial metabolism. L-carnitine and acylcarnitines are established mitochondrial biomarkers used to screen neonates for a series of genetic disorders affecting fatty acid oxidation, known as the inborn errors of metabolism. However, L-carnitine and acylcarnitines are not routinely measured beyond this screening, despite the growing evidence that shows their clinical utility outside of these disorders. Measurements of the carnitine pool have been used to identify the disease and prognosticate mortality among disorders such as diabetes, sepsis, cancer, and heart failure, as well as identify subjects experiencing adverse drug reactions from various medications like valproic acid, clofazimine, zidovudine, cisplatin, propofol, and cyclosporine. The aim of this review is to collect and interpret the literature evidence supporting the clinical biomarker application of L-carnitine and acylcarnitines. Further study of these metabolites could ultimately provide mechanistic insights that guide therapeutic decisions and elucidate new pharmacologic targets.
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Affiliation(s)
- Marc R. McCann
- The NMR Metabolomics Laboratory, Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Mery Vet George De la Rosa
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA; (M.V.G.); (G.R.R.)
| | - Gus R. Rosania
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA; (M.V.G.); (G.R.R.)
| | - Kathleen A. Stringer
- The NMR Metabolomics Laboratory, Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA;
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Michigan Center for Integrative Research in Critical Care, University of Michigan, Ann Arbor, MI 48109, USA
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21
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Jennaro TS, Puskarich MA, McCann MR, Gillies CE, Pai MP, Karnovsky A, Evans CR, Jones AE, Stringer KA. Using l-Carnitine as a Pharmacologic Probe of the Interpatient and Metabolic Variability of Sepsis. Pharmacotherapy 2020; 40:913-923. [PMID: 32688453 DOI: 10.1002/phar.2448] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The objective of this review is to discuss the therapeutic use and differential treatment response to Levo-carnitine (l-carnitine) treatment in septic shock, and to demonstrate common lessons learned that are important to the advancement of precision medicine approaches to sepsis. We propose that significant interpatient variability in the metabolic response to l-carnitine and clinical outcomes can be used to elucidate the mechanistic underpinnings that contribute to sepsis heterogeneity. METHODS A narrative review was conducted that focused on explaining interpatient variability in l-carnitine treatment response. Relevant biological and patient-level characteristics considered include genetic, metabolic, and morphomic phenotypes; potential drug interactions; and pharmacokinetics (PKs). MAIN RESULTS Despite promising results in a phase I study, a recent phase II clinical trial of l-carnitine treatment in septic shock showed a nonsignificant reduction in mortality. However, l-carnitine treatment induces significant interpatient variability in l-carnitine and acylcarnitine concentrations over time. In particular, administration of l-carnitine induces a broad, dynamic range of serum concentrations and measured peak concentrations are associated with mortality. Applied systems pharmacology may explain variability in drug responsiveness by using patient characteristics to identify pretreatment phenotypes most likely to derive benefit from l-carnitine. Moreover, provocation of sepsis metabolism with l-carnitine offers a unique opportunity to identify metabolic response signatures associated with patient outcomes. These approaches can unmask latent metabolic pathways deranged in the sepsis syndrome and offer insight into the pathophysiology, progression, and heterogeneity of the disease. CONCLUSIONS The compiled evidence suggests there are several potential explanations for the variability in carnitine concentrations and clinical response to l-carnitine in septic shock. These serve as important confounders that should be considered in interpretation of l-carnitine clinical studies and broadly holds lessons for future clinical trial design in sepsis. Consideration of these factors is needed if precision medicine in sepsis is to be achieved.
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Affiliation(s)
- Theodore S Jennaro
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Michael A Puskarich
- Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA.,Department of Emergency Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Marc R McCann
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Christopher E Gillies
- Department of Emergency Medicine, University of Michigan, Ann Arbor, Michigan, USA.,Michigan Center for Integrative Research in Critical Care (MCIRCC), School of Medicine, University of Michigan, Ann Arbor, Michigan, USA.,Michigan Institute for Data Science, Office of Research, University of Michigan, Ann Arbor, Michigan, USA
| | - Manjunath P Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.,Michigan Center for Integrative Research in Critical Care (MCIRCC), School of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Alla Karnovsky
- Department of Computational Medicine and Bioinformatics, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Charles R Evans
- Michigan Regional Comprehensive Metabolomics Resource Core (MRC2), University of Michigan, Ann Arbor, Michigan, USA.,Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Alan E Jones
- Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Kathleen A Stringer
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.,Michigan Center for Integrative Research in Critical Care (MCIRCC), School of Medicine, University of Michigan, Ann Arbor, Michigan, USA.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, Michigan, USA
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22
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Abdollahi H, Abdolahi M, Sedighiyan M, Jafarieh A. The Effect of L-Carnitine on Mortality Rate in Septic Patients: A Systematic Review and Meta-Analysis on Randomized Clinical Trials. Endocr Metab Immune Disord Drug Targets 2020; 21:673-681. [PMID: 32718301 DOI: 10.2174/1871530320666200727150450] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 05/20/2020] [Accepted: 05/29/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Recent clinical trial studies have reported that L-carnitine supplementation can reduce the mortality rate in patients with sepsis, but there are no definitive results in this context. The current systematic review and meta-analysis aimed to evaluate the effect of L-carnitine supplementation on 28-day and one-year mortality in septic patients. METHODS A systematic search conducted on Pubmed, Scopus and Cochrane Library databases up to June 2019 without any language restriction. The publications were reviewed based on the Cochrane handbook and preferred reporting items for systematic reviews and meta-analyses (PRISMA). To compare the effects of L-carnitine with placebo, Risk Ratio (RR) with 95% confidence intervals (CI) were pooled according to the random effects model. RESULTS Across five enrolled clinical trials, we found that L-carnitine supplementation reduce one-year mortality in septic patients with SOFA> 12 (RR: 0.68; 95% CI: 0.49 to 0.96; P= 0.03) but had no significant effect on reducing 28-day mortality ((RR: 0.93; 95% CI: 0.68 to 1.28; P= 0.65) compared to placebo. Finally, we observed that based on current trials, L-carnitine supplementation may not have clinically a significant effect on mortality rate. CONCLUSION L-carnitine patients with higher SOFA score can reduce the mortality rate. However, the number of trials, study duration and using a dosage of L-carnitine are limited in this context and further large prospective trials are required to clarify the effect of L-carnitine on mortality rate in septic patients.
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Affiliation(s)
- Hamed Abdollahi
- Department of Anesthesiology, Amir Alam Hospital Complexes, Sa'adi Street, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Abdolahi
- Department of Anesthesiology, Amir Alam Hospital Complexes, Sa'adi Street, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Sedighiyan
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Poursina Street, Tehran University of Medical Sciences, Tehran, Iran
| | - Arash Jafarieh
- Department of Anesthesiology, Amir Alam Hospital Complexes, Sa'adi Street, Tehran University of Medical Sciences, Tehran, Iran
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23
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Lactated Ringer's Versus 4% Albumin on Lactated Ringer's in Early Sepsis Therapy in Cancer Patients: A Pilot Single-Center Randomized Trial. Crit Care Med 2020; 47:e798-e805. [PMID: 31356475 DOI: 10.1097/ccm.0000000000003900] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To investigate the effects of the administration of 4% albumin on lactated Ringer's, when compared with lactated Ringer's alone, in the early phase of sepsis in cancer patients. DESIGN Single-center, randomized, double-blind, controlled-parallel trial. SETTING A tertiary care university cancer hospital. PATIENTS Cancer patients with severe sepsis or septic shock. INTERVENTIONS Between October 2014 and December 2016, patients were randomly assigned to receive either bolus of albumin in a lactated Ringer's solution or lactated Ringer's solution alone during the first 6 hours of fluid resuscitation after intensive care medicine (ICU) admission. Primary outcome was defined as death from any cause at 7 days. Secondary outcomes were defined as death from any cause within 28 days, change in Sequence Organ Failure Assessment scores from baseline to day 7, days alive and free of mechanical ventilation, days alive and free of vasopressor, renal replacement therapy during ICU stay, and length of ICU and hospital stay. MEASUREMENTS AND MAIN RESULTS A total of 360 patients were enrolled in the trial. At 7 days, 46 of 180 patients (26%) died in the albumin group and 40 of 180 (22%) died in the lactated Ringer's group (p = 0.5). At 28 days, 96 of 180 patients (53%) died in the albumin group and 83 of 180 (46%) died in the lactated Ringer's group (p = 0.2). No significant differences in secondary outcomes were observed. CONCLUSIONS Adding albumin to early standard resuscitation with lactated Ringer's in cancer patients with sepsis did not improve 7-day survival.
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24
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ALSUntangled 53: Carnitine supplements. Amyotroph Lateral Scler Frontotemporal Degener 2020; 21:477-483. [PMID: 32046513 DOI: 10.1080/21678421.2020.1726565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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25
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Micronutrient deficiency in critical illness: an invisible foe? Intensive Care Med 2019; 45:1136-1139. [PMID: 31338529 DOI: 10.1007/s00134-019-05678-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 06/24/2019] [Indexed: 01/28/2023]
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26
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Evans CR, Karnovsky A, Puskarich MA, Michailidis G, Jones AE, Stringer KA. Untargeted Metabolomics Differentiates l-Carnitine Treated Septic Shock 1-Year Survivors and Nonsurvivors. J Proteome Res 2019; 18:2004-2011. [PMID: 30895797 DOI: 10.1021/acs.jproteome.8b00774] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
l-Carnitine is a candidate therapeutic for the treatment of septic shock, a condition that carries a ≥40% mortality. Responsiveness to l-carnitine may hinge on unique metabolic profiles that are not evident from the clinical phenotype. To define these profiles, we performed an untargeted metabolomic analysis of serum from 21 male sepsis patients enrolled in a placebo-controlled l-carnitine clinical trial. Although treatment with l-carnitine is known to induce changes in the sepsis metabolome, we found a distinct set of metabolites that differentiated 1-year survivors from nonsurvivors. Following feature alignment, we employed a new and innovative data reduction strategy followed by false discovery correction, and identified 63 metabolites that differentiated carnitine-treated 1-year survivors versus nonsurvivors. Following identification by MS/MS and database search, several metabolite markers of vascular inflammation were determined to be prominently elevated in the carnitine-treated nonsurvivor cohort, including fibrinopeptide A, allysine, and histamine. While preliminary, these results corroborate that metabolic profiles may be useful to differentiate l-carnitine treatment responsiveness. Furthermore, these data show that the metabolic signature of l-carnitine-treated nonsurvivors is associated with a severity of illness (e.g., vascular inflammation) that is not routinely clinically detected.
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Affiliation(s)
| | | | - Michael A Puskarich
- Department of Emergency Medicine, Hennepin County Medical Center, and Department of Emergency Medicine, School of Medicine , University of Minnesota , Minneapolis , Minnesota 55455 , United States
| | - George Michailidis
- Department of Statistics, College of Literature, Science and Art , University of Michigan and the Informatics Institute University of Florida , Gainesville , Flordia 32611 , United States
| | - Alan E Jones
- Emergency Medicine , University of Mississippi Medical Center , Jackson , Mississippi 39216 , United States
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Septic Shock Nonsurvivors Have Persistently Elevated Acylcarnitines Following Carnitine Supplementation. Shock 2019; 49:412-419. [PMID: 29384504 DOI: 10.1097/shk.0000000000000997] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Sepsis-induced metabolic disturbances include hyperlactatemia, disruption of glycolysis, protein catabolism, and altered fatty acid metabolism. It may also lower serum L-carnitine that supports the use of L-carnitine supplementation as a treatment to ameliorate several of these metabolic consequences. METHODS To further understand the association between L-carnitine-induced changes in serum acylcarnitines, fatty acid metabolism and survival, serum samples from (T0), 12 hfollowing completion (T24) of L-carnitine (n = 16) or placebo (n = 15) administration, and 48 h (T48) after enrollment from patients with septic shock enrolled in a randomized control trial were assayed for acylcarnitines, free fatty acids, and insulin. Data were analyzed comparing 1-year survivors and nonsurvivors within treatment groups. RESULTS Mortality was 8 of 16 (50%) and 12 of 15 (80%) at 1 year for L-carnitine and placebo-treated patients, respectively. Free carnitine, C2, C3, and C8 acylcarnitines were higher among nonsurvivors at enrollment. L-Carnitine treatment increased levels of all measured acylcarnitines; an effect that was sustained for at least 36 h following completion of the infusion and was more prominent among nonsurvivors. Several fatty acids followed a similar, though less consistent pattern. Glucose, lactate, and insulin levels did not differ based on survival or treatment arm. CONCLUSIONS In human patients with septic shock, L-Carnitine supplementation increases a broad range of acylcarnitine concentrations that persist after cessation of infusion, demonstrating both immediate and sustained effects on the serum metabolome. Nonsurvivors demonstrate a distinct metabolic response to L-carnitine compared with survivors, which may indicate preexisting or more profound metabolic derangement that constrains any beneficial response to treatment.
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28
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Increased Plasma Acetylcarnitine in Sepsis Is Associated With Multiple Organ Dysfunction and Mortality. Crit Care Med 2019; 47:210-218. [DOI: 10.1097/ccm.0000000000003517] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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29
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Jones AE, Puskarich MA, Shapiro NI, Guirgis FW, Runyon M, Adams JY, Sherwin R, Arnold R, Roberts BW, Kurz MC, Wang HE, Kline JA, Courtney DM, Trzeciak S, Sterling SA, Nandi U, Patki D, Viele K. Effect of Levocarnitine vs Placebo as an Adjunctive Treatment for Septic Shock: The Rapid Administration of Carnitine in Sepsis (RACE) Randomized Clinical Trial. JAMA Netw Open 2018; 1:e186076. [PMID: 30646314 PMCID: PMC6324339 DOI: 10.1001/jamanetworkopen.2018.6076] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
IMPORTANCE Sepsis induces profound metabolic derangements, while exogenous levocarnitine mitigates metabolic dysfunction by enhancing glucose and lactate oxidation and increasing fatty acid shuttling. Previous trials in sepsis suggest beneficial effects of levocarnitine on patient-centered outcomes. OBJECTIVES To test the hypothesis that levocarnitine reduces cumulative organ failure in patients with septic shock at 48 hours and, if present, to estimate the probability that the most efficacious dose will decrease 28-day mortality in a pivotal phase 3 clinical trial. DESIGN, SETTING, AND PARTICIPANTS Multicenter adaptive, randomized, blinded, dose-finding, phase 2 clinical trial (Rapid Administration of Carnitine in Sepsis [RACE]). The setting was 16 urban US medical centers. Participants were patients aged 18 years or older admitted from March 5, 2013, to February 5, 2018, with septic shock and moderate organ dysfunction. INTERVENTIONS Within 24 hours of identification, patients were assigned to 1 of the following 4 treatments: low (6 g), medium (12 g), or high (18 g) doses of levocarnitine or an equivalent volume of saline placebo administered as a 12-hour infusion. MAIN OUTCOMES AND MEASURES The primary outcome required, first, a greater than 90% posterior probability that the most promising levocarnitine dose decreases the Sequential Organ Failure Assessment (SOFA) score at 48 hours and, second (given having met the first condition), at least a 30% predictive probability of success in reducing 28-day mortality in a subsequent traditional superiority trial to test efficacy. RESULTS Of the 250 enrolled participants (mean [SD] age, 61.7 [14.8] years; 56.8% male), 35, 34, and 106 patients were adaptively randomized to the low, medium, and high levocarnitine doses, respectively, while 75 patients were randomized to placebo. In the intent-to-treat analysis, the fitted mean (SD) changes in the SOFA score for the low, medium, and high levocarnitine groups were -1.27 (0.49), -1.66 (0.38), and -1.97 (0.32), respectively, vs -1.63 (0.35) in the placebo group. The posterior probability that the 18-g dose is superior to placebo was 0.78, which did not meet the a priori threshold of 0.90. Mortality at 28 days was 45.9% (34 of 74) in the placebo group compared with 43.3% (45 of 104) for the most promising levocarnitine dose (18 g). Similar findings were noted in the per-protocol analysis. CONCLUSIONS AND RELEVANCE In this dose-finding, phase 2 adaptive randomized trial, the most efficacious dose of levocarnitine (18 g) did not meaningfully reduce cumulative organ failure at 48 hours. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01665092.
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Affiliation(s)
- Alan E. Jones
- Department of Emergency Medicine, The University of Mississippi Medical Center, Jackson
| | - Michael A. Puskarich
- Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota
| | - Nathan I. Shapiro
- Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Faheem W. Guirgis
- Department of Emergency Medicine, University of Florida College of Medicine–Jacksonville
| | - Michael Runyon
- Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina
| | - Jason Y. Adams
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of California, Davis
| | - Robert Sherwin
- Department of Emergency Medicine, Wayne State University, Detroit, Michigan
| | - Ryan Arnold
- Department of Emergency Medicine, Christiana Care Health System, Wilmington, Delaware
| | - Brian W. Roberts
- Department of Emergency Medicine, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, New Jersey
| | - Michael C. Kurz
- Department of Emergency Medicine, The University of Alabama School of Medicine at Birmingham
| | - Henry E. Wang
- Department of Emergency Medicine, The University of Texas Health Science Center at Houston
| | - Jeffrey A. Kline
- Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis
| | - D. Mark Courtney
- Department of Emergency Medicine, Northwestern University, Chicago, Illinois
| | - Stephen Trzeciak
- Department of Medicine, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, New Jersey
| | - Sarah A. Sterling
- Department of Emergency Medicine, The University of Mississippi Medical Center, Jackson
| | - Utsav Nandi
- Department of Emergency Medicine, The University of Mississippi Medical Center, Jackson
| | - Deepti Patki
- Department of Emergency Medicine, The University of Mississippi Medical Center, Jackson
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Wan YD, Zhu RX, Wu ZQ, Lyu SY, Zhao LX, Du ZJ, Pan XT. Gut Microbiota Disruption in Septic Shock Patients: A Pilot Study. Med Sci Monit 2018; 24:8639-8646. [PMID: 30488879 PMCID: PMC6282651 DOI: 10.12659/msm.911768] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND The composition of the intestinal microbiota and its effect on septic shock patients in the intensive care unit (ICU) is unknown. In the present study we explored the hypothesis that bacterial diversity is decreased in septic shock patients and that this diversity may be improved by use of probiotics or enteral nutrition. MATERIAL AND METHODS A total of 15 stool samples were collected prospectively from septic shock patients in the ICU, while 15 samples from healthy subjects served as controls. Bacterial DNA was submitted for 16S rDNA gene sequencing. The relationship between intestinal microbiota and prognosis was evaluated. RESULTS Significantly lower bacterial diversity was found in septic shock patients compared with healthy subjects (p<0.05). However, there was no difference in bacterial diversity in the presence or absence of probiotics (p=0.59), enteral nutrition (p=0.59), or in-hospital death (p=0.93) in septic shock patients. A high abundance of Proteobacteria and Fusobacteria was observed in most septic shock patients, whereas low abundance was observed in healthy subjects (mean relative proportion: 23.71% vs. 3.53%, p<0.05; 1.27% vs. 0.12%, p=0.59). CONCLUSIONS Bacterial diversity was decreased, and 1 or 2 rare bacterial species were overgrown in septic shock patients. Bacterial diversity was not improved by use of probiotics or enteral nutrition. The small sample size of our study limits the interpretation of results.
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Affiliation(s)
- You-Dong Wan
- Department of Emergency, Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Rui-Xue Zhu
- Department of Ultrasound, Zhengzhou Central Hospital, Zhengzhou, Henan, China (mainland)
| | - Zi-Qian Wu
- Department of Emergency, Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Shao-Yan Lyu
- Department of Emergency, Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Lian-Xing Zhao
- Department of Emergency, Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Zhong-Jun Du
- Department of Emergency, Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Xin-Ting Pan
- Department of Emergency, Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
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Marik PE. Hydrocortisone, Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid. Nutrients 2018; 10:nu10111762. [PMID: 30441816 PMCID: PMC6265973 DOI: 10.3390/nu10111762] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 10/30/2018] [Accepted: 11/08/2018] [Indexed: 12/21/2022] Open
Abstract
Sepsis is a devastating disease that carries an enormous toll in terms of human suffering and lives lost. Over 100 novel pharmacologic agents that targeted specific molecules or pathways have failed to improve the outcome of sepsis. Preliminary data suggests that the combination of Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) may reduce organ failure and mortality in patients with sepsis and septic shock. HAT therapy is based on the concept that a combination of readily available, safe and cheap agents, which target multiple components of the host’s response to an infectious agent, will synergistically restore the dysregulated immune response and thereby prevent organ failure and death. This paper reviews the rationale for HAT therapy with a focus on vitamin C.
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Affiliation(s)
- Paul E Marik
- Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
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32
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Nabzdyk CS, Bittner EA. Vitamin C in the critically ill - indications and controversies. World J Crit Care Med 2018; 7:52-61. [PMID: 30370227 PMCID: PMC6201324 DOI: 10.5492/wjccm.v7.i5.52] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 08/04/2018] [Accepted: 08/21/2018] [Indexed: 02/06/2023] Open
Abstract
Ascorbic acid (vitamin C) elicits pleiotropic effects in the body. Among its functions, it serves as a potent anti-oxidant, a co-factor in collagen and catecholamine synthesis, and a modulator of immune cell biology. Furthermore, an increasing body of evidence suggests that high-dose vitamin C administration improves hemodynamics, end-organ function, and may improve survival in critically ill patients. This article reviews studies that evaluate vitamin C in pre-clinical models and clinical trials with respect to its therapeutic potential.
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Affiliation(s)
- Christoph S Nabzdyk
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Edward A Bittner
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
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33
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A review of micronutrients in sepsis: the role of thiamine, l-carnitine, vitamin C, selenium and vitamin D. Nutr Res Rev 2018; 31:281-290. [PMID: 29984680 DOI: 10.1017/s0954422418000124] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Sepsis is defined as the dysregulated host response to an infection resulting in life-threatening organ dysfunction. The metabolic demand from inefficiencies in anaerobic metabolism, mitochondrial and cellular dysfunction, increased cellular turnover, and free-radical damage result in the increased focus of micronutrients in sepsis as they play a pivotal role in these processes. In the present review, we will evaluate the potential role of micronutrients in sepsis, specifically, thiamine, l-carnitine, vitamin C, Se and vitamin D. Each micronutrient will be reviewed in a similar fashion, discussing its major role in normal physiology, suspected role in sepsis, use as a biomarker, discussion of the major basic science and human studies, and conclusion statement. Based on the current available data, we conclude that thiamine may be considered in all septic patients at risk for thiamine deficiency and l-carnitine and vitamin C to those in septic shock. Clinical trials are currently underway which may provide greater insight into the role of micronutrients in sepsis and validate standard utilisation.
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Hogan P, Plourde R, Fortier M, Brindamour D, Lagrenade-Verdant C, Demers-Marcil S, Dupuis S. Refractory Hyperlactatemia After a Septic Shock in a Patient With Carnitine Deficiency: A Case Report. J Pharm Pract 2018; 33:113-116. [PMID: 29905091 DOI: 10.1177/0897190018782012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A 56-year-old woman with septic shock presented with persistent hyperlactatemia, despite an adequate clinical response to treatment. Carnitine deficiency was suspected, as the patient was malnourished and chronically taking valproic acid. No other plausible cause of hyperlactatemia was found. Carnitine supplementation resulted in rapid normalization of lactatemia.
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Affiliation(s)
- Philippe Hogan
- Faculté de pharmacie, Université de Montréal, Montréal, Quebec, Canada.,Department of pharmacy, Hôpital du Sacré-Cœur-de-Montréal, Montréal, Quebec, Canada
| | - Roxane Plourde
- Faculté de pharmacie, Université de Montréal, Montréal, Quebec, Canada.,Department of pharmacy, Hôpital du Sacré-Cœur-de-Montréal, Montréal, Quebec, Canada
| | - Maude Fortier
- Faculté de pharmacie, Université de Montréal, Montréal, Quebec, Canada.,Department of pharmacy, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
| | - Dave Brindamour
- Department of pharmacy, Hôpital du Sacré-Cœur-de-Montréal, Montréal, Quebec, Canada
| | - Colin Lagrenade-Verdant
- Faculté de médecine, Université de Montréal, Montréal, Quebec, Canada.,Department of critical care, Hôpital du Sacré-Cœur-de-Montréal, Montréal, Quebec, Canada
| | | | - Sébastien Dupuis
- Department of pharmacy, Hôpital du Sacré-Cœur-de-Montréal, Montréal, Quebec, Canada.,Research center, Hôpital du Sacré-Cœur-de-Montréal, Montréal, Quebec, Canada
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Oami T, Oshima T, Hattori N, Teratani A, Honda S, Yoshida T, Oda S. l-carnitine in critically ill patients—a case series study. RENAL REPLACEMENT THERAPY 2018. [DOI: 10.1186/s41100-018-0158-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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de Grooth HJ, Postema J, Loer SA, Parienti JJ, Oudemans-van Straaten HM, Girbes AR. Unexplained mortality differences between septic shock trials: a systematic analysis of population characteristics and control-group mortality rates. Intensive Care Med 2018; 44:311-322. [PMID: 29546535 PMCID: PMC5861172 DOI: 10.1007/s00134-018-5134-8] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 02/17/2018] [Indexed: 12/21/2022]
Abstract
Purpose Although the definition of septic shock has been standardized, some variation in mortality rates among clinical trials is expected. Insights into the sources of heterogeneity may influence the design and interpretation of septic shock studies. We set out to identify inclusion criteria and baseline characteristics associated with between-trial differences in control group mortality rates. Methods We conducted a systematic review of RCTs published between 2006 and 2018 that included patients with septic shock. The percentage of variance in control-group mortality attributable to study heterogeneity rather than chance was measured by I2. The association between control-group mortality and population characteristics was estimated using linear mixed models and a recursive partitioning algorithm. Results Sixty-five septic shock RCTs were included. Overall control-group mortality was 38.6%, with significant heterogeneity (I2 = 93%, P < 0.0001) and a 95% prediction interval of 13.5–71.7%. The mean mortality rate did not differ between trials with different definitions of hypotension, infection or vasopressor or mechanical ventilation inclusion criteria. Population characteristics univariately associated with mortality rates were mean Sequential Organ Failure Assessment score (standardized regression coefficient (β) = 0.57, P = 0.007), mean serum creatinine (β = 0.48, P = 0.007), the proportion of patients on mechanical ventilation (β = 0.61, P < 0.001), and the proportion with vasopressors (β = 0.57, P = 0.002). Combinations of population characteristics selected with a linear model and recursive partitioning explained 41 and 42%, respectively, of the heterogeneity in mortality rates. Conclusions Among 65 septic shock trials, there was a clinically relevant amount of heterogeneity in control group mortality rates which was explained only partly by differences in inclusion criteria and reported baseline characteristics. Electronic supplementary material The online version of this article (10.1007/s00134-018-5134-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Harm-Jan de Grooth
- Department of Intensive Care, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
- Department of Anesthesiology, VU University Medical Center, Amsterdam, The Netherlands.
| | - Jonne Postema
- Department of Anesthesiology, VU University Medical Center, Amsterdam, The Netherlands
| | - Stephan A Loer
- Department of Anesthesiology, VU University Medical Center, Amsterdam, The Netherlands
| | - Jean-Jacques Parienti
- Unité de Biostatistique et de Recherche Clinique, Centre Hospitalier Universitaire de Caen, Caen, France
- EA2656 Groupe de Recherche sur l'Adaptation Microbienne (GRAM 2.0), Université Caen Normandie, Caen, France
| | | | - Armand R Girbes
- Department of Intensive Care, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
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Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med 2017; 45:486-552. [PMID: 28098591 DOI: 10.1097/ccm.0000000000002255] [Citation(s) in RCA: 1943] [Impact Index Per Article: 242.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.
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Sepsis: frontiers in supportive care, organisation and research. Intensive Care Med 2017; 43:496-508. [DOI: 10.1007/s00134-017-4677-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 01/03/2017] [Indexed: 01/05/2023]
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Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017; 43:304-377. [PMID: 28101605 DOI: 10.1007/s00134-017-4683-6] [Citation(s) in RCA: 3913] [Impact Index Per Article: 489.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 01/06/2017] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.
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Puskarich MA, Shapiro NI, Massey MJ, Kline JA, Jones AE. Lactate Clearance in Septic Shock Is Not a Surrogate for Improved Microcirculatory Flow. Acad Emerg Med 2016; 23:690-3. [PMID: 26825368 DOI: 10.1111/acem.12928] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 11/30/2015] [Accepted: 12/23/2015] [Indexed: 12/29/2022]
Abstract
BACKGROUND Failure to normalize lactate is associated with poor outcomes in septic shock. It has been suggested that persistently elevated lactate may result from regional ischemia due to disturbed and/or heterogenous microcirculatory blood flow. OBJECTIVES The goal of this study was to determine if lactate clearance (LC) may serve as a surrogate marker for changes in microcirculatory blood flow in patients with septic shock. METHODS This was a prospective observational study performed within a previously published clinical trial of l-carnitine for the treatment of vasopressor-dependent septic shock. Intravital video microscopy was performed at enrollment and 12 hours later, and microcirculatory flow index (MFI) was assessed. Associations between enrollment MFI, lactate, and Sequential Organ Failure Assessment (SOFA) score were determined, in addition to associations between ∆MFI, LC, and ∆SOFA. A preplanned subgroup analysis of only patients with an elevated initial lactate was performed. RESULTS We enrolled a total of 31 patients, 23 with survival and sufficient quality videos both at enrollment and at 12 hours. ∆MFI, LC, and ∆SOFA were 0.1 (interquartile range [IQR] = 0 to 0.3), 18% (IQR = -10% to 46%), and -2 (IQR = -4 to 0). Both ∆MFI and LC were associated with ∆SOFA (β = -5.3, p = 0.01; and β = -3.5, 0.047), but not with each other, even in the subgroup of patients with an initially elevated lactate. CONCLUSIONS We observed no association between degree of LC and change in microcirculatory blood flow in patients with septic shock. These data suggest against the hypothesis that LC may be used as a surrogate marker of microcirculatory blood flow.
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Affiliation(s)
- Michael A. Puskarich
- Carolinas Medical Center; Charlotte NC
- Department of Emergency Medicine; University of Mississippi Medical Center; Jackson MS
| | - Nathan I. Shapiro
- Department of Emergency Medicine; Beth Israel Deaconess Medical Center; Boston MA
| | - Michael J. Massey
- Department of Emergency Medicine; Beth Israel Deaconess Medical Center; Boston MA
| | - Jeffrey A. Kline
- Department of Emergency Medicine; University of Indiana School of Medicine; Indianapolis IN
| | - Alan E. Jones
- Department of Emergency Medicine; University of Mississippi Medical Center; Jackson MS
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Swaminathan S, Rosner MH, Okusa MD. Emerging therapeutic targets of sepsis-associated acute kidney injury. Semin Nephrol 2015; 35:38-54. [PMID: 25795498 DOI: 10.1016/j.semnephrol.2015.01.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Sepsis-associated acute kidney injury (SA-AKI) is linked to high morbidity and mortality. To date, singular approaches to target specific pathways known to contribute to the pathogenesis of SA-AKI have failed. Because of the complexity of the pathogenesis of SA-AKI, a reassessment necessitates integrative approaches to therapeutics of SA-AKI that include general supportive therapies such as the use of vasopressors, fluids, antimicrobials, and target-specific and time-dependent therapeutics. There has been recent progress in our understanding of the pathogenesis and treatment of SA-AKI including the temporal nature of proinflammatory and anti-inflammatory processes. In this review, we discuss the clinical and experimental basis of emerging therapeutic approaches that focus on targeting early proinflammatory and late anti-inflammatory processes, as well as therapeutics that may enhance cellular survival and recovery. Finally, we include ongoing clinical trials in sepsis.
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Affiliation(s)
- Sundararaman Swaminathan
- Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA
| | - Mitchell H Rosner
- Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA
| | - Mark D Okusa
- Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA.
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Pharmacometabolomics of l-carnitine treatment response phenotypes in patients with septic shock. Ann Am Thorac Soc 2015; 12:46-56. [PMID: 25496487 DOI: 10.1513/annalsats.201409-415oc] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
RATIONALE Sepsis therapeutics have a poor history of success in clinical trials, due in part to the heterogeneity of enrolled patients. Pharmacometabolomics could differentiate drug response phenotypes and permit a precision medicine approach to sepsis. OBJECTIVES To use existing serum samples from the phase 1 clinical trial of l-carnitine treatment for severe sepsis to metabolically phenotype l-carnitine responders and nonresponders. METHODS Serum samples collected before (T0) and after completion of the infusion (T24, T48) from patients randomized to either l-carnitine (12 g) or placebo for the treatment of vasopressor-dependent septic shock were assayed by untargeted (1)H-nuclear magnetic resonance metabolomics. The normalized, quantified metabolite data sets of l-carnitine- and placebo-treated patients at each time point were compared by analysis of variance with post-hoc testing for multiple comparisons. Pathway analysis was performed to statistically rank metabolic networks. MEASUREMENTS AND MAIN RESULTS Thirty-eight metabolites were identified in all samples. Concentrations of 3-hydroxybutyrate, acetoacetate, and 3-hydroxyisovalerate were different at T0 and over time in l-carnitine-treated survivors versus nonsurvivors. Pathway analysis of pretreatment metabolites revealed that synthesis and degradation of ketone bodies had the greatest impact in differentiating l-carnitine treatment response. Analysis of all patients based on pretreatment 3-hydroxybutyrate concentration yielded distinct phenotypes. Using the T0 median 3-hydroxybutyrate level (153 μM), patients were categorized as either high or low ketone. l-Carnitine-treated low-ketone patients had greater use of carnitine as evidenced by lower post-treatment l-carnitine levels. The l-carnitine responders also had faster resolution of vasopressor requirement and a trend toward a greater improvement in mortality at 1 year (P = 0.038) compared with patients with higher 3-hydroxybutyrate. CONCLUSIONS The results of this preliminary study, which were not readily apparent from the parent clinical trial, show a unique metabolite profile of l-carnitine responders and introduce pharmacometabolomics as a viable strategy for informing l-carnitine responsiveness. The approach taken in this study represents a concrete example for the application of precision medicine to sepsis therapeutics that warrants further study.
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Rech MA, Day SA, Kast JM, Donahey EE, Pajoumand M, Kram SJ, Erdman MJ, Peitz GJ, Allen JM, Palmer A, Kram B, Harris SA, Turck CJ. Major publications in the critical care pharmacotherapy literature: January-December 2013. Am J Health Syst Pharm 2015; 72:224-36. [PMID: 25596607 DOI: 10.2146/ajhp140241] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
PURPOSE Ten recently published articles with important implications for critical care pharmacotherapy are summarized. SUMMARY The Critical Care Pharmacotherapy Literature Update (CCPLU) group is a national assembly of experienced intensive care unit (ICU) pharmacists across the United States. Group members monitor 25 peer-reviewed journals on an ongoing basis to identify literature relevant to pharmacy practice in the critical care setting. After evaluation by CCPLU group members, selected articles are chosen for summarization and distribution to group members nationwide based on (1) applicability to critical care practice, (2) relevance to pharmacy practitioners, and (3) quality of evidence or research methodology. Hundreds of relevant articles were evaluated by the group during the period January-December 2013, of which 98 were summarized and disseminated nationally to CCPLU group members. Among those 98 publications, 10 deemed to be of particularly high utility to critical care practitioners were included in this review. The 10 articles address topics such as rapid lowering of blood pressure in patients with intracranial hemorrhage, adjunctive therapy to prevent renal injury due to acute heart failure, triple-drug therapy to improve neurologic outcomes after cardiac arrest, and continuous versus intermittent infusion of β-lactam antibiotics in severe sepsis. CONCLUSION There were many important additions to the critical care pharmacotherapy literature in 2013, including an updated guideline on the management of myocardial infarction and reports on advances in research focused on improving outcomes in patients with stroke or cardiac arrest and preventing the spread of drug-resistant pathogens in the ICU.
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Affiliation(s)
- Megan A Rech
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA.
| | - Sarah A Day
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
| | - Jenna M Kast
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
| | - Elisabeth E Donahey
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
| | - Mehrnaz Pajoumand
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
| | - Shawn J Kram
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
| | - Michael J Erdman
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
| | - Gregory J Peitz
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
| | - John M Allen
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
| | - Allison Palmer
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
| | - Bridgette Kram
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
| | - Serena A Harris
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
| | - Charles J Turck
- Megan A. Rech, Pharm.D., BCPS, is Emergency Medicine Clinical Pharmacist, Loyola University Medical Center, Maywood, IL. Sarah A. Day, Pharm.D., BCPS, is Clinical Pharmacist, Critical Care, Doctors Hospital, Columbus, OH. Jenna M. Kast, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Critical Care, Beaumont Hospital, Royal Oak, MI. Elisabeth E. Donahey, Pharm.D., BCPS, is Neurosciences Intensive Care Pharmacist, Loyola University Medical Center. Mehrnaz Pajoumand, Pharm.D., BCPS, is Clinical Specialist, Trauma Critical Care, University of Maryland Medical Center, Baltimore. Shawn J. Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital, Durham, NC. Michael J. Erdman, Pharm.D., BCPS, is Clinical Pharmacist, Neurocritical Care, University of Florida Health, Jacksonville. Gregory J. Peitz, Pharm.D., BCPS, is Clinical Assistant Professor, Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha. John M. Allen, Pharm.D., BCPS, is Assistant Professor, University of South Florida College of Pharmacy, Tampa. Allison Palmer, Pharm.D., BCPS, is Critical Care Clinical Pharmacist, John Peter Smith Hospital, Fort Worth, TX. Bridgette Kram, Pharm.D., BCPS, is Clinical Pharmacist, Duke University Hospital. Serena A. Harris, Pharm.D., BCPS, is Clinical Pharmacy Specialist, Trauma and Surgical Critical Care, Eskenazi Health, Indianapolis, IN. Charles J Turck, Pharm.D., BCPS, is President and Chief Executive Officer, ScientiaCME, LLC, Mission Viejo, CA
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To KKW, Lee KC, Wong SSY, Lo KC, Lui YM, Jahan AS, Wu AL, Ke YH, Law CY, Sze KH, Lau SKP, Woo PCY, Lam CW, Yuen KY. Lipid mediators of inflammation as novel plasma biomarkers to identify patients with bacteremia. J Infect 2015; 70:433-44. [PMID: 25727996 DOI: 10.1016/j.jinf.2015.02.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Revised: 02/16/2015] [Accepted: 02/20/2015] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Rapid diagnostic tests for bacteremia are important for early treatment to improve clinical outcome. We sought to identify plasma biomarkers that can identify patients with bacteremia using an untargeted global metabolomic analysis. METHODS Plasma metabolomic profiles were analyzed for 145 adult patients with (cases) and without (controls) bacteremia using ultra-high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). All metabolites were compared between cases and controls using a 2-tier filtering approach, and each metabolite underwent receiver operating characteristic (ROC) curve analysis. Individual metabolites that distinguish between cases and controls were characterized. Subgroup analysis was performed to identify metabolites with prognostic significance. RESULTS After 2-tier filtering, 128 molecular features were identified to be potential biomarkers that could distinguish cases from controls. Five metabolites had an area under the ROC curve (AUC) of >0.8 in ROC curve analysis, including a sphingolipid, an acylcarnitine, a fatty acid ester, and 2 glycerophosphocholines. These metabolites could distinguish cases from controls in the unsupervised hierarchical clustering analysis. Subgroup analysis of bacteremic patients showed that the level of trans-2,3,4-trimethoxycinnamate was lower in fatal than non-fatal cases. CONCLUSIONS Plasma lipid mediators of inflammation can distinguish bacteremia cases from non-bacteremia controls. These biomarkers may be used as targets for rapid test in clinical practice.
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Affiliation(s)
- Kelvin K W To
- State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China; Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Kim-Chung Lee
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Samson S Y Wong
- State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China; Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Ka-Ching Lo
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Yin-Ming Lui
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Akhee S Jahan
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Andrea L Wu
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Yi-Hong Ke
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Chun-Yiu Law
- Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - Kong-Hung Sze
- Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Susanna K P Lau
- State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China; Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Patrick C Y Woo
- State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China; Department of Microbiology, The University of Hong Kong, Hong Kong, China
| | - Ching-Wan Lam
- Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - Kwok-Yung Yuen
- State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China; Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China; Department of Microbiology, The University of Hong Kong, Hong Kong, China.
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