Summary of Study ST000785

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000571. The data can be accessed directly via it's Project DOI: 10.21228/M8VM2M This work is supported by NIH grant, U2C- DK119886.

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Study IDST000785
Study TitlePharmacometabolomics of L-Carnitine Treatment Response Phenotypes in Patients with Septic Shock
Study Typemultiple timepoints; patients with severe sepsis or septic shock
Study Summaryphase I study of L-carnitine infusion for the treatment of vasopressor-dependent shock
Institute
University of Michigan
DepartmentClinical Pharmacy
LaboratoryThe NMR Metabolomics Laboratory (Stringer)
Last NameStringer
First NameKathleen
AddressUniversity Michigan, 2900 Huron Parkway, Ann Arbor, MI 48105
EmailNMRmetabolomics@umich.edu
Phonenone
Submit Date2016-12-08
Num Groups2
Total Subjects31
Raw Data AvailableYes
Raw Data File Type(s)fid
Analysis Type DetailNMR
Release Date2017-10-03
Release Version1
Kathleen Stringer Kathleen Stringer
https://dx.doi.org/10.21228/M8VM2M
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR000571
Project DOI:doi: 10.21228/M8VM2M
Project Title:Pharmacometabolomics of L-Carnitine Treatment for Septic Shock
Project Type:Quantitative NMR Metabolomics
Project Summary: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. Objective: To utilize existing serum samples from the phase I clinical trial of L-carnitine treatment for severe sepsis to metabolically phenotype L-carnitine responders and non-responders. Methods: Serum samples collected prior to (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 1H-nuclear magnetic resonance metabolomics. The normalized, quantified metabolite data sets of L-carnitine and placebo treated patients at each time point were compared by ANOVA with post-hoc testing for multiple comparisons. Pathway analysis was performed to statistically rank metabolic networks. Measurements and main results: 38 metabolites were identified in all samples. Concentrations of 3-hydroxybutyrate, acetoacetate, 3-hydroxyisovalerate were different at T0 and over time in L-carnitine treated survivors versus non-survivors. Pathway analysis of pre-treatment 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 pre-treatment 3-hydroxybutyrate concentration yielded distinct phenotypes. Using the T0 median 3-hydroxybutyrate level (153µM), patients were categorized as either high or low ketone. L-carnitine treated low ketone patients had greater utilization 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 towards 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, that 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. This study was published: Ann Am Thorac Soc 2015;12:46-56.
Institute:University of Michigan
Department:Emergency Medicine
Laboratory:University of Michigan NMR Metabolomics Laboratory
Last Name:Stringer
First Name:Kathleen
Address:College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109
Email:NMRmetabolomics@umich.edu
Phone:none
Funding Source:This study was supported by the University of Michigan’s College of Pharmacy and its Biochemical Nuclear Magnetic Resonance Core and in part by the Michigan Regional Comprehensive Metabolomics Research Core (AK and Chenomx software), which is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; DK097153). The clinical trial was supported by a grant from the American Heart Association (10POST3560001) and the Cannon Foundation (SRG10-004). Dr. Jones’ effort was supported by a grant from the National Institute of General Medicine (NIGMS; R01GM103799). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDDK, NIGMS or the National Institutes of Health. NIDDK (DK097153).

Subject:

Subject ID:SU000808
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Age Or Age Range:39-93 years
Weight Or Weight Range:55-130 KG
Gender:males and females
Human Race:Caucasian (C) and African American (AA)
Human Inclusion Criteria:Suspicion of or confirmed infection; two or more systemic infmammatory response syndrome criteria; hypotension requiring vasopressors despite volume resuscitation; a cumulative vasopressor index of 3 or more after 4 hours of administration; and a SOFA score of at least 5.
Human Exclusion Criteria:Age less than 18; greater than 16h after septic shock recognition; a Do Not Resuscitate order; or known inborn error of metaboloism.
Species Group:Human

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Treatment
SA042817CMC2020-0Carnitine
SA042818CMC2017-48Carnitine
SA042819CMC2020-24Carnitine
SA042820CMC2021-0Carnitine
SA042821CMC2021-24Carnitine
SA042822CMC2017-24Carnitine
SA042823CMC2020-48Carnitine
SA042824CMC2017-0Carnitine
SA042825CMC2013-48Carnitine
SA042826CMC2013-24Carnitine
SA042827CMC2001-0Carnitine
SA042828CMC2016-24Carnitine
SA042829CMC2016-48Carnitine
SA042830CMC2024-0Carnitine
SA042831CMC2024-48Carnitine
SA042832CMC2029-24Carnitine
SA042833CMC2029-0Carnitine
SA042834CMC2029-48Carnitine
SA042835CMC2031-0Carnitine
SA042836CMC2031-48Carnitine
SA042837CMC2031-24Carnitine
SA042838CMC2027-48Carnitine
SA042839CMC2027-24Carnitine
SA042840CMC2025-0Carnitine
SA042841CMC2013-0Carnitine
SA042842CMC2025-24Carnitine
SA042843CMC2025-48Carnitine
SA042844CMC2027-0Carnitine
SA042845CMC2024-24Carnitine
SA042846CMC2016-0Carnitine
SA042847CMC2009-48Carnitine
SA042848CMC2006-48Carnitine
SA042849CMC2009-24Carnitine
SA042850CMC2009-0Carnitine
SA042851CMC2007-24Carnitine
SA042852CMC2007-0Carnitine
SA042853CMC2004-24Carnitine
SA042854CMC2004-48Carnitine
SA042855CMC2011-0Carnitine
SA042856CMC2001-48Carnitine
SA042857CMC2001-24Carnitine
SA042858CMC2006-0Carnitine
SA042859CMC2006-24Carnitine
SA042860CMC2007-48Carnitine
SA042861CMC2004-0Carnitine
SA042862CMC2026-48Placebo
SA042863CMC2026-24Placebo
SA042864CMC2005-0Placebo
SA042865CMC2026-0Placebo
SA042866CMC2028-24Placebo
SA042867CMC2030-24Placebo
SA042868CMC2030-48Placebo
SA042869CMC2002-24Placebo
SA042870CMC2002-0Placebo
SA042871CMC2030-0Placebo
SA042872CMC2002-48Placebo
SA042873CMC2028-0Placebo
SA042874CMC2005-24Placebo
SA042875CMC2003-24Placebo
SA042876CMC2003-0Placebo
SA042877CMC2003-48Placebo
SA042878CMC2023-0Placebo
SA042879CMC2015-0Placebo
SA042880CMC2015-24Placebo
SA042881CMC2015-48Placebo
SA042882CMC2010-0Placebo
SA042883CMC2014-48Placebo
SA042884CMC2014-24Placebo
SA042885CMC2012-24Placebo
SA042886CMC2012-0Placebo
SA042887CMC2014-0Placebo
SA042888CMC2008-48Placebo
SA042889CMC2008-24Placebo
SA042890CMC2022-0Placebo
SA042891CMC2012-48Placebo
SA042892CMC2023-24Placebo
SA042893CMC2023-48Placebo
SA042894CMC2008-0Placebo
SA042895CMC2019-48Placebo
SA042896CMC2018-0Placebo
SA042897CMC2019-0Placebo
SA042898CMC2019-24Placebo
SA042899CMC2005-48Placebo
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Collection:

Collection ID:CO000802
Collection Summary:Serum collected via existing intravenous or arterial catheter
Collection Protocol Comments:T0: collected before carnitine or placebo administration, T24: collected 24h after administration of L-carnitine or placebo (±4h), T48: collected 48h after administration of L-carnitine or placebo (±4h)
Sample Type:Blood serum
Collection Method:via existing intravenous or arterial catheter
Collection Frequency:1/timepoint, 3 collections/48h
Collection Time:T0: before administration, T24: 24h after administration (±4h), T48: 48h after administration (±4h)
Volumeoramount Collected:10mL
Storage Conditions:Initial RT then -80°C following processing (within 2h of collection)
Collection Vials:SST: Becton-Dickinson 10mL vacutainer Serum Separator tubes
Storage Vials:Sterile 1mL cryovials
Collection Tube Temp:RT
Additives:None
Blood Serum Or Plasma:Serum

Treatment:

Treatment ID:TR000822
Treatment Summary:Intravenous carnitine
Treatment Protocol Comments:Non-treatment group: equivalent volume of saline placebo
Treatment Compound:L-carnitine
Treatment Route:4g bolus followed by an 8g infusion over 12h
Treatment Dose:12g
Treatment Doseduration:12h (following initial 4g bolus)

Sample Preparation:

Sampleprep ID:SP000815
Sampleprep Summary:Methanol:cholorform extraction, filtration
Sampleprep Protocol Comments:Lipid fractions saved, stored at -20°C
Processing Method:Methanol:Chloroform Extraction, filtration
Processing Storage Conditions:0-4°C
Extraction Method:Methanol:chloroform extraction
Extract Enrichment:Ultra-filtration (3kDa filters) to remove residual protein
Extract Cleanup:N/A
Extract Storage:-80 C
Sample Resuspension:=500 uL Deuterium Oxide (D2O)
Sample Spiking:CaFormate 12mM

Analysis:

Analysis ID:AN001244
Laboratory Name:University of Michigan Biochemical NMR Core Laboratory
Analysis Type:NMR
Software Version:VNMRJ 3.2
Operator Name:Michael Finkel, Julie Trexel
Detector Type:NMR
Data Format:.FID
Num Factors:2
Num Metabolites:38
Units:µM

NMR:

NMR ID:NM000105
Analysis ID:AN001244
Instrument Name:Agilent 500/54 Premium Shielded VNMRS system
Instrument Type:FT-NMR
NMR Experiment Type:1D 1H
NMR Comments:Experiment dates: 11/7/2013, 11/11/2013, 11/19/2013
Standard Concentration:10% (~0.5mM)
Spectrometer Frequency:500 MHz
NMR Probe:ONE-Probe
NMR Solvent:D2O
NMR Tube Size:5mm
Shimming Method:Auto shim (gradient shimming)
Pulse Sequence:1D-NOESY
Water Suppression:saturation at 80 Hz induced field strength
Pulse Width:5.5ms
Power Level:around -178Hz
Chemical Shift Ref Cpd:Formate
Temperature:25°C
Number Of Scans:32
Baseline Correction Method:manual
Chemical Shift Ref Std:Calcium Formate
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