Pharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock

Puskarich, Michael A.; Jennaro, Theodore S.; Gillies, Christopher E.; Evans, Charles R.; Karnovsky, Alla; McHugh, Cora; Flott, Thomas L.; Jones, Alan E.; Stringer, Kathleen A.; Investigators, Race Trial

doi:10.1111/cts.13088

Cited by 11 publications

(19 citation statements)

References 52 publications

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“…We excluded patients who were allocated to receive intravenous L-carnitine to focus on the metabolic trajectory of the disease course without any interference that may be introduced by the study drug. Furthermore, we have previously identified phenotypes of L-carnitine response ( 19 ). The trial protocol was approved by the institutional review board (IRB) of all 16 centers and registered with clinicaltrials.gov (NCT01665092) prior to patient enrollment.…”

Section: Methodsmentioning

confidence: 99%

“…Serum was obtained from whole blood, frozen at –80°C, and shipped on dry ice to the University of Michigan College of Pharmacy Nuclear Magnetic Resonance (NMR) Metabolomics Laboratory to await metabolomics assays. Further details regarding sample processing from this trial have been reported elsewhere ( 19 , 26 ).…”

Section: Methodsmentioning

confidence: 99%

“…For our analysis, we used existing metabolomics data that were generated as part of an ancillary metabolomics study to the RACE trial ( 19 ). We employed the same metabolomics strategy as our prior work, which included the measurement of low-molecular-weight, polar metabolites as measured by NMR spectroscopy using previously described methods ( 18 ).…”

Section: Methodsmentioning

confidence: 99%

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Sustained Perturbation of Metabolism and Metabolic Subphenotypes Are Associated With Mortality and Protein Markers of the Host Response

Jennaro

Puskarich

Evans

et al. 2023

Critical Care Explorations

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Perturbed host metabolism is increasingly recognized as a pillar of sepsis pathogenesis, yet the dynamic alterations in metabolism and its relationship to other components of the host response remain incompletely understood. We sought to identify the early host-metabolic response in patients with septic shock and to explore biophysiological phenotyping and differences in clinical outcomes among metabolic subgroups. DESIGN:We measured serum metabolites and proteins reflective of the hostimmune and endothelial response in patients with septic shock. SETTING:We considered patients from the placebo arm of a completed phase II, randomized controlled trial conducted at 16 U.S. medical centers. Serum was collected at baseline (within 24 hr of the identification of septic shock), 24-hour, and 48-hour postenrollment. Linear mixed models were built to assess the early trajectory of protein analytes and metabolites stratified by 28-day mortality status. Unsupervised clustering of baseline metabolomics data was conducted to identify subgroups of patients. PATIENTS:Patients with vasopressor-dependent septic shock and moderate organ dysfunction that were enrolled in the placebo arm of a clinical trial. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:Fifty-one metabolites and 10 protein analytes were measured longitudinally in 72 patients with septic shock. In the 30 patients (41.7%) who died prior to 28 days, systemic concentrations of acylcarnitines and interleukin (IL)-8 were elevated at baseline and persisted at T24 and T48 throughout early resuscitation. Concentrations of pyruvate, IL-6, tumor necrosis factor-α, and angiopoietin-2 decreased at a slower rate in patients who died. Two groups emerged from clustering of baseline metabolites. Group 1 was characterized by higher levels of acylcarnitines, greater organ dysfunction at baseline and postresuscitation (p < 0.05), and greater mortality over 1 year (p < 0.001).CONCLUSIONS: Among patients with septic shock, nonsurvivors exhibited a more profound and persistent dysregulation in protein analytes attributable to neutrophil activation and disruption of mitochondrial-related metabolism than survivors.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Sustained Perturbation of Metabolism and Metabolic Subphenotypes Are Associated With Mortality and Protein Markers of the Host Response

Jennaro

Puskarich

Evans

et al. 2023

Critical Care Explorations

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“…Detailed descriptions of the blood sampling, handling, and processing from this cohort have been previously reported [26,30]. Briefly, baseline whole blood samples were collected at the time of clinical trial enrollment.…”

Section: Blood Sampling and Metabolomicsmentioning

confidence: 99%

“…Metabolomics, as an applied science, identifies small molecules in a biological sample [20]. In doing so, metabolomics provides a physiological "snapshot" and molecular phenotype of the host and has proven useful in differentiating patient outcomes and response to drug therapy in patients with sepsis [21][22][23][24][25][26][27]. As such, we sought to determine among mechanically ventilated patients with septic shock, if the baseline patient metabolic status could help distinguish CCI from patients with rapid recovery.…”

Section: Introductionmentioning

confidence: 99%

Serum Levels of Acylcarnitines and Amino Acids Are Associated with Liberation from Organ Support in Patients with Septic Shock

Jennaro

Viglianti

Ingraham

et al. 2022

JCM

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Sepsis-induced metabolic dysfunction is associated with mortality, but the signatures that differentiate variable clinical outcomes among survivors are unknown. Our aim was to determine the relationship between host metabolism and chronic critical illness (CCI) in patients with septic shock. We analyzed metabolomics data from mechanically ventilated patients with vasopressor-dependent septic shock from the placebo arm of a recently completed clinical trial. Baseline serum metabolites were measured by liquid chromatography-mass spectrometry and 1H-nuclear magnetic resonance. We conducted a time-to-event analysis censored at 28 days. Specifically, we determined the relationship between metabolites and time to extubation and freedom from vasopressors using a competing risk survival model, with death as a competing risk. We also compared metabolite concentrations between CCI patients, defined as intensive care unit level of care ≥ 14 days, and those with rapid recovery. Elevations in two acylcarnitines and four amino acids were related to the freedom from organ support (subdistributional hazard ratio < 1 and false discovery rate < 0.05). Proline, glycine, glutamine, and methionine were also elevated in patients who developed CCI. Our work highlights the need for further testing of metabolomics to identify patients at risk of CCI and to elucidate potential mechanisms that contribute to its etiology.

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Kidney function as a key driver of the pharmacokinetic response to high‐dose L‐carnitine in septic shock

Jennaro,

Puskarich,

Flott

et al. 2023

Pharmacotherapy

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Study ObjectiveLevocarnitine (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.DesignPopulation 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 SourceWe 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 InterventionPatients were adaptively randomized to receive intravenous L‐carnitine (6 grams, 12 grams, or 18 grams) or placebo.Measurements and Main ResultsThe 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.ConclusionsHigh‐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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Pharmacometabolomics identifies candidate predictor metabolites of an L‐carnitine treatment mortality benefit in septic shock

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 11 publications

References 52 publications

Sustained Perturbation of Metabolism and Metabolic Subphenotypes Are Associated With Mortality and Protein Markers of the Host Response

Sustained Perturbation of Metabolism and Metabolic Subphenotypes Are Associated With Mortality and Protein Markers of the Host Response

Serum Levels of Acylcarnitines and Amino Acids Are Associated with Liberation from Organ Support in Patients with Septic Shock

Kidney function as a key driver of the pharmacokinetic response to high‐dose L‐carnitine in septic shock

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