EP2912161A2 - Procédés et systèmes pour estimer les besoins nutritionnels de patients humains et d'autres patients et pour prendre en charge de tels besoins nutritionnels - Google Patents

Procédés et systèmes pour estimer les besoins nutritionnels de patients humains et d'autres patients et pour prendre en charge de tels besoins nutritionnels

Info

Publication number
EP2912161A2
EP2912161A2 EP13848522.2A EP13848522A EP2912161A2 EP 2912161 A2 EP2912161 A2 EP 2912161A2 EP 13848522 A EP13848522 A EP 13848522A EP 2912161 A2 EP2912161 A2 EP 2912161A2
Authority
EP
European Patent Office
Prior art keywords
formulation
patient
glucose
lactate
gluconeogenesis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP13848522.2A
Other languages
German (de)
English (en)
Other versions
EP2912161A4 (fr
Inventor
Michael Horning
George Brooks
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Run Them Sweet LLC
Original Assignee
Run Them Sweet LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US13/903,929 external-priority patent/US9808031B2/en
Priority claimed from US14/043,703 external-priority patent/US9232815B2/en
Priority claimed from US14/061,640 external-priority patent/US9897609B2/en
Application filed by Run Them Sweet LLC filed Critical Run Them Sweet LLC
Priority to EP19151852.1A priority Critical patent/EP3505167A1/fr
Publication of EP2912161A2 publication Critical patent/EP2912161A2/fr
Publication of EP2912161A4 publication Critical patent/EP2912161A4/fr
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/30—Dietetic or nutritional methods, e.g. for losing weight
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0029—Parenteral nutrition; Parenteral nutrition compositions as drug carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals

Definitions

  • PROTOCOLS TO SUPPORT PATIENTS SYSTEM S AND APPARATUS TO ESTIMATE NUTRITIONAL NEEDS OF HUMAN AND OTHER PATIENTS AND TO SUPPORT SUCH NUTRITIONAL NEEDS
  • PROTOCOLS TO SUPPORT PATIENTS SYSTEM S AND APPARATUS TO ESTIMATE NUTRITIONAL NEEDS OF HUMAN AND OTHER PATIENTS AND TO SUPPORT SUCH NUTRITIONAL NEEDS
  • the present disclosure generally relates to the field of medical treatment. More specifically, the invention presents systems and methods to ascertain the metabolic state and nutritional needs of a patient, which can be thought of as the body energy state ("BES") of the patient. Assessment of the BES of the patient is critical information to treat and nourish (feed) the patient appropriately. Such assessment is based on ongoing and dynamic estimates of the biomarker fractional gluconeogenesis, which is the % of body glucose production that comes from gluconeogenesis. Methods, systems and materials for patient nutritional treatment and feeding based on estimation of this biomarker are also provided.
  • BES body energy state
  • Glucose is a basic fuel of the human body (as well as of many other organisms) and is delivered throughout the body through the blood.
  • the rate of glucose production also referred to as glucose rate of appearance and glucose Ra, is about 2-3 mg/min/kg of body weight in a healthy person while at rest, and can be as high as 8 mg/min/kg or more under stress such as exercise or illness.
  • Pyruvate and lactate which are both gluconeogenic precursors and products of glucose catabolism, are also basic fuels of the human body and other organisms.
  • Glucose a six-carbon (hexose) sugar
  • hexose a six-carbon sugar
  • glucose is an important and tightly regulated metabolite.
  • Glucose Ra should not be confused with blood concentration of glucose, also called [glucose].
  • the latter is a simple measure of the total amount of glucose in the blood, as opposed to the rate of production.
  • the [glucose] is a common measurement taken from a blood samples, as in standard doctor office visits and home diabetes diagnostics. This value can vary significantly in resting individuals, but generally averages about 90- 100 mg/dl blood or 5.5 mM.
  • glucose can appear in the blood of a person by three major means: delivery from ingested carbohydrate- containing foods, hepatic glycogenolysis (“GLY”), and gluconeogenesis (“GNG”) (hepatic and renal).
  • GLY hepatic glycogenolysis
  • GNG gluconeogenesis
  • the recommended dietary allowance for carbohydrate-containing foods is about 130 g/day, a value determined to be the minimal daily brain glucose requirement (8) (note that non-patent literature citations are made as numbers in parentheses, and the corresponding references are listed at the end of this specification).
  • dietary carbohydrate and total nutrient inadequacy will reflexively cause increased GLY and GNG to maintain glucose requirements for the brain, other tissues with high glucose needs (nerves, red blood cells, kidneys) and the body in general.
  • GLY Glucose production occurs by GLY and GNG. It is generally better if the majority of glucose production is from GLY. This is because GLY is an efficient process of glucose production, in that it is simple breakdown of glycogen, a glucose polymer stored mainly in the muscles, liver and kidneys. Normally, at rest, in a nourished state, most glucose is produced by GLY (typically over 75%). This number can decrease under stress such as exercise or illness, as the body needs to produce more glucose than can be provided by GLY.
  • GNG Gluconeogenesis
  • GLY glycogenolysis
  • GNG glycogen stored elsewhere in the body instead of direct conversion of that glycogen to glucose.
  • the biomarker [glucose] is well known in the art and simple to assess from a blood test. While a large shift (either low or high) in [glucose] can be cause for concern and inform the type of feeding the patient receives, it does not provide a good indicator of the BES of a patient, especially within its typical ranges. Indeed, the maintenance of blood glucose homeostasis is a top physiological priority, and there are diverse and redundant body mechanisms to maintain blood [glucose] . Thus a normal [glucose] may belie metabolic stresses that are going on, with the body working very hard to maintain [glucose]. Among those mechanisms are GNG, a critically important process about which the blood [glucose] measurement provides no direct information.
  • Ra glucose rate of appearance
  • a biomarker indicates that the patient may be experiencing a stress (such as injury, exercise or starvation) that has induced a high glucose production. While this is a somewhat useful, there is need for a biomarker that is a more precise indicator of BES. In addition, determination of glucose Ra is complex, time consuming and costly.
  • labeled glucose typically glucose with deuterium (typically noted as simply D or 2 H as opposed to merely H, hydrogen) , or carbon 13 ( 13 C), and comparison of labeled and non-labeled glucose (the latter produced by the glucose pathways) to determine Ra (80) .
  • a priming bolus of perhaps about 125 times the continuous per minute infusion rate, or about 250 mg D2-glucose, is infused over several min prior to
  • isotopic equilibration in the blood can be achieved in 60-90 min (about half the time to isotopic equilibration in blood if a priming tracer dose is not given).
  • PCA perchloric acid
  • GC/MS gas chromatography/ mass spectrometry
  • a labeled internal standard such as uniformly labeled glucose, where each carbon of the glucose is labeled, by for example, the carbon 13 isotope, thus noted [U- 13 C]glucose
  • the glucose molecule thus has an increased mass of about 6 atomic units (“au”) (m+6).
  • This labeled glucose is added to the supernatant of control subject or patient samples collected in perchloric acid.
  • samples are neutralized with 2N KOH and transferred to cation resin, ion exchange columns such as 50W-X8 (from Bio-Rad Laboratories).
  • Glucose is eluted first with doubly deionized 3 ⁇ 40 (the anions, and cations, by contrast, are retained on the column).
  • the glucose ion-exchange effluent is reduced by lyophilization and derivatized by resuspending the lyophilized sample in a small amount (e.g., 1 ml) of methanol, a small amount [e.g., 200 microliter (ml)] is transferred to a 2 ml microreaction vial and dried under N gas.
  • a small amount (e.g., 100 ml) of a 2: 1 acetic anhydride-pyridine solution is added to each sample vial and heated at 60°C for 10 min. Samples are again dried under N2 gas, resuspended in a small amount (e.g., 200 ml) of ethyl acetate, and transferred to micro vials for analysis.
  • Glucose isotopic enrichment (“IE") is determined by GC/MS, for instance with a GC model 6890 series and MS model 5973N, from Agilent Technologies) of the penta- acetate derivative, where methane is used for selected ion monitoring of mass-to-charge ratios (m/z) 331 (non-labeled glucose), 332 (M+ l isotopomer, [ l- 13 C]glucose), 333 (M+2 isotopomer, D2-glucose), and 337 (M+6 isotopomer, [U- 13 C]glucose, the internal standard). Whole blood glucose concentration is determined by abundance ratios of 331 /337.
  • the invention presents systems and methods to ascertain the metabolic state and nutritional needs of a patient. Such assessment is based on ongoing and dynamic estimates of the biomarker fractional gluconeogenesis, which is the % of body glucose production that comes from gluconeogenesis. Methods, systems and materials for patient nutritional treatment and feeding based on estimation of this biomarker are also provided.
  • the invention includes, but is not limited to the following, with some variation.
  • the invention provides a method for estimating the fractional gluconeogenesis of a patient, administering a label to the patient, taking a blood sample from the patient, analyzing glucose or a glucose derivative from the blood sample, obtaining a value for fractional gluconeogenesis based on abundance from one or more mass spectra, obtaining a value for fractional
  • gluconeogenesis plus glycogenolysis from one or more mass spectra, and estimating fractional gluconeogenesis.
  • the invention provides a method for providing nutritional support to a patient, including administering a label to the patient, taking a blood sample from the patient, analyzing glucose or a glucose derivative from the blood sample, obtaining a value for fractional gluconeogenesis based on abundance from one or more mass spectra, obtaining a value for fractional
  • gluconeogenesis plus glycogenolysis from one or more mass spectra using the value to create to estimate fractional gluconeogenesis, and administering a parenteral nutritive formulation to the patient based upon the fractional gluconeogenesis estimate.
  • the label may be deuterium.
  • the invention provides a method for estimating the fractional gluconeogenesis of a patient, the method including, administering a label to the patient, estimating the fraction of body water that has been labeled, using this estimate to create a baseline for the amount of total glucose production, estimating an amount of glucose production only from gluconeogenesis by measuring the label, and estimating the patient's fractional gluconeogenesis.
  • the methods can include a water labeled with deuterium, wherein less than about 1% of the body water is labeled, wherein the body water is labeled with an initial bolus, wherein the body water is continually labeled by ongoing infusion of labeled water, wherein the glucose derivative is a penta-acetate glucose molecule with molecular weight of about 390, wherein part of the estimation is based on the abundance of the label on one or more of glucose carbons 1 , 3, 4, 5, 6, wherein part of the estimation is based on the abundance of the label on glucose carbon 2, wherein glucose Ra is estimated to further provide an estimate of absolute rate of GNG, and using a correction factor to correct for the fraction of the molecule that exists in a state that includes the label.
  • the method provides for molecule analysis in a gas chromatograph mass spectrometer.
  • the method provides, upon estimating the fractional gluconeogenesis, the patient is administered a parenteral nutritive formulation, wherein the formulation may contain MCC or GNG precursor or both, pyruvate or lactate or both, wherein the formulation is administered or increased if the estimated fractional GNG is above about 25% or 35%, wherein the formulation is stopped or decreased if the estimated fractional GNG is below about 15% or 20%.
  • the invention provides a parenteral nutritive formulation for feeding a patient to decrease or stabilize fractional gluconeogenesis, including water and MCC or GNG precursor or both. It also provides a parenteral nutritive formulation for feeding a patient with injury or illness, including water and MCC or GNG precursor or both. It also provides parenteral nutritive
  • formulations for feeding a patient to decrease or stabilize fractional gluconeogenesis including water and lactate or pyruvate or both, and one or more salts, wherein the formulation has an osmolality less than about 310 mOsm.
  • the formulations may also include one or more salts, one or more of Na + , K + , Ca ++ , Mg ++ , and H2PO4", a label such as deuterium, have an osmolality of less than about 310 mOsm, where one of the MCCs or GNGs is lactate or pyruvate or both, where one of the MCCs or GNGs is an amino acid where one of the MCCs or GNGs is a GNG precursor that naturally occurs in the body, where one of the MCCs or GNGs is a compound that does not naturally occur in the body but that can be used as a GNG precursor, where one of the MCCs or GNGs is glycerol or glycerol tri-lactate.
  • the formulation may be administered at a rate of about 3 mg/kg/min, where kg is kg of patient body weight and 3 mg is the amount of MCC or GNG in the formulation, may be administered at a rate of about 50 micro moles per kg of body weight per minute (mMoles/kg/ min), where kg is kg of patient body weight and 50 mM is the amount of MCC or GNG in the formulation, administered or increased if estimated fractional GNG is above about 25% or 35%, or decreased or stopped if estimate of fractional gluconeogenesis is below about 20% or 15%.
  • mMoles/kg/ min micro moles per kg of body weight per minute
  • the formulations may include a label such as deuterium and one or more salts. They may contain or more of the following: Na+, K + , Ca ++ , Mg ++ , and H2PO4". They may have Na + , K + , Ca ++ , Mg ++ , and H 2 P0 4 - provided in the ratio of about 145, 4, 2.5, 1.5, and 1.0 respectively. They may have MCC or GNG precursor or both. The formulation may have an osmolality of less than about 310 mOsm.
  • the formulation may have an MCCs or GNGs that is lactate or pyruvate or both, an amino acid, a GNG precursor that naturally occurs in the body, a compound that does not naturally occur in the body but that can be used as a GNG precursor, glycerol tri-lactate or arginyl lactate.
  • the formulation may be administered at a rate of about 3 mg/kg/ min, where kg is kg of patient body weight and 3mg is the amount of MCC or GNG precursor in the formulation and may be administered or increased if estimated fractional GNG is above about 25% or 35%, or decreased or stopped if estimate of fractional gluconeogenesis is below about 20% or 15%.
  • the formulations may be parenteral, used to estimate fractional GNG, used to stabilize or decrease fractional GNG.
  • the label may be incorporated into glucose.
  • the label may be differentially incorporated into glucose depending on whether it is incorporated via the gluconeogenesis pathway or via the glycogenolysis pathway.
  • the nutritive formulations may include deuterium, lactate or pyruvate or both, and one or more salts, may have an osmolality of less than about 310 mOsm, may have one more of the following: Na+, K + , Ca ++ , Mg ++ , and H 2 PC -, may be parenteral.
  • the nutritive formulation may be used to decrease or stabilize fractional gluconeogenesis, and include deuterium, lactate or pyruvate or both, and one or more salts, may have an osmolality of less than about 310 mOsm, and may have one more of the following: Na + , K + , Ca ++ , Mg ++ , and H 2 P0 4 -.
  • various labels may be used, including deuterium, such as in deuterium oxide (water), and sometimes at a concentration of less than about 1% of the water.
  • the formulations may be enteral or parenteral.
  • the invention provides a method for estimating the fractional gluconeogenesis of a patient, the method including, from a patient blood sample, analyzing the glucose or one or more derivatives of the glucose, or both, the blood sample comprising glucose and a label, obtaining a value or set of values for gluconeogenesis, obtaining a value or set of values for total glucose production, and the above to estimate fractional gluconeogenesis.
  • the invention provides a method for estimating the fractional gluconeogenesis of a patient, including, from a patient blood sample, analyzing the glucose or one or more derivatives of the glucose, or both, the blood sample comprising glucose and a label, estimating the fraction of body water that has been labeled, using this to create a baseline for the amount of total glucose production; estimating an amount of glucose production from gluconeogenesis by measuring the label and using above to estimate the fractional gluconeogenesis.
  • the invention provides a method for aiding in the estimation of the fractional gluconeogenesis of a patient, the method including, from a patient blood sample, analyzing the glucose or one or more derivatives of the glucose, or both, the blood sample comprising glucose and a label, obtaining a value or set of values for gluconeogenesis based on the abundance of the label on one or more of glucose carbons 1 , 3, 4, 5, 6, and obtaining a value or set of values for total glucose production based on the abundance of the label on glucose carbon 2.
  • the method further includes transmitting these values or sets of values and using them to calculate a value or set of values for estimated fractional gluconeogenesis.
  • the invention provides a method for aiding in the estimation of the fractional gluconeogenesis of a patient, the method including from a patient blood sample, analyzing the glucose or one or more derivatives of the glucose, or both, the blood sample comprising glucose and a label, estimating the fraction of body water that has been labeled, using this estimating to obtain a value or set of values as a baseline for the amount of total glucose production and obtaining a value or set of values for gluconeogenesis by measuring the label.
  • the method also includes transmitting the value or set of values obtained and using them to calculate a value or set of values for estimated fractional gluconeogenesis.
  • the invention provides a method for estimating the fractional gluconeogenesis of a patient, the method including receiving a value or set of values for gluconeogenesis, receiving a value or set of values for total glucose production, using (a) and (b) to estimate fractional gluconeogenesis.
  • the invention provides a method for estimating the fractional gluconeogenesis of a patient, the method including receiving a value or set of values for gluconeogenesis, receiving a value or set of values for fraction of body water that has been labeled and using the above to estimate fractional gluconeogenesis.
  • the invention provides a method of providing nutrition to a patient, the method including obtaining a value or set of values for estimated fractional gluconeogenesis, and decreasing, increasing or maintaining nutritional support based on the value or set of values for estimated fractional gluconeogenesis.
  • Nutritional support may be stopped or decrease if the value or set of values for estimated fractional gluconeogenesis is above about 25%.
  • Nutritional support is begun or increased if the value or set of values for estimated fractional gluconeogenesis is below about 15%.
  • the invention provides a method of providing nutritional support to a patient, the method including, (a)
  • administering a label (b) administering a formulation, (c) taking one or more blood samples from the patient, and (d) measuring incorporation of the label into glucose in order to estimate fractional gluconeogenesis.
  • method (c) and (d) may be done on a periodic basis in order to provide an ongoing estimate of fractional gluconeogenesis.
  • the invention provides a method for estimating the fractional gluconeogenesis of a patient, the method including, ( 1) administering a label, (b) administering a formulation, (c) taking one or more blood samples from the patient, (d) analyzing glucose or a glucose derivative from the blood sample, (e) obtaining a value for fractional gluconeogenesis, (f) obtaining a value for fractional gluconeogenesis plus glycogenolysis, and (g) using (e) and (f) to estimate fractional gluconeogenesis.
  • the method (c)-(g) are done on a periodic basis in order to provide an ongoing estimate of fractional gluconeogenesis.
  • the invention provides a method for estimating the fractional gluconeogenesis of a patient, the method including, (a) administering a label, (b) administering a formulation, (c) taking one or more blood samples from the patient, (d) estimating the fraction of body water that has been labeled, (e) using the estimating in (d) to create a baseline for the amount of total glucose production, (f) estimating an amount of glucose production only from gluconeogenesis by measuring the label, and (g) using (e) and (f) to estimate the patient's fractional gluconeogenesis.
  • the method (c)-(g) are done on a periodic basis in order to provide an ongoing estimate of fractional gluconeogenesis.
  • the invention provides a method of modulating the fractional gluconeogenesis of a patient, the method including: (a) administering a label, (b) administering a formulation, (c) taking one or more blood samples from the patient, (d) measuring incorporation of the label into glucose in order to estimate fractional gluconeogenesis, and (e) modifying the composition and rate of infusion or both of the formulation to target a fractional gluconeogenesis range.
  • the gluconeogenesis range targeted may be about 15-35% or about 20-25%.
  • the invention provides a method of providing nutritional support to a patient, the method including, (a) estimating the blood lactate concentration of the patient, (b) providing, increasing, decreasing or ceasing a formulation to the patient based on the blood lactate
  • the invention provides a method of targeting a blood lactate concentration in a patient, the method including, (a) estimating the blood lactate concentration of the patient, and (b) increasing, decreasing or maintaining or ceasing a formulation to achieve the target blood lactate concentration.
  • the invention provides a method of affecting the fractional gluconeogenesis of a patient, the method including: (a) estimating the blood lactate concentration of the patient, (b) increasing, decreasing or maintaining a first formulation to achieve a target blood lactate concentration, (c) estimating the fractional gluconeogenesis of the patient, and (d) providing a second formulation to the patient in order to achieve a target fractional gluconeogenesis range.
  • the invention provides a formulation including: (a) GNG precursor or MCC or both, and (b) one or more salts, the formulation capable of affecting blood lactate concentration.
  • the invention provides a formulation including: (a) GNG precursor or MCC or both, the formulation capable of reducing or stabilizing catabolism or cachexia or both.
  • the formulations of the invention throughout are capable of affecting blood lactate concentration, capable of reducing or stabilizing catabolism and cachexia.
  • the formulations may include glucose polymer.
  • the invention provides method of providing nutritional support to a patient, the method including: (a) providing a formulation comprising a GNG precursor or MCC or both, wherein the formulation is capable of affecting the blood lactate concentration of the patient, and may target a blood lactate concentration is above about 1 -8 mM.
  • the invention provides a formulation for providing nutritional support for physical activity, the formulation including: GNG precursor or MCC or both, and one or more salts.
  • the invention provides method of providing nutritional support for physical activity, the method including providing a formulation comprising a GNG precursor or MCC or both and one or more salts, and may target a blood lactate concentration is above about 1 -8 mM.
  • the method and formulations of the invention may label the body water with an initial bolus or ongoing infusion or both.
  • the value or set of values for total glucose production can also represent % body water labeled, and can be based on the abundance of the label on one or more of glucose carbons 1 , 3, 4, 5, 6.
  • the value or set of values for gluconeogenesis can be based on the abundance of the label on glucose carbon 2.
  • the glucose derivative analyzed is a penta-acetate glucose molecule with molecular weight of about 390, or has a molecular weight of about 169, or 172.
  • the value or set of may include a correction factor.
  • Glucose Ra may be estimated to further provide an estimate of absolute rate of gluconeogenesis.
  • the formulation of the method may include GNG precursor or MCC or both, pyruvate or lactate or both, a GNG precursor or MCC other than lactate.
  • the formulation may be administered or increased if the estimated fractional gluconeogenesis is above about 25%.
  • the formulation may be stopped or decreased if the estimated fractional gluconeogenesis is below about 20%.
  • the methods and formulations may have Na+, K + , Ca ++ , Mg ++ , and H 2 P0 4 Na + , K + , Ca ++ , Mg ++ , and 3 ⁇ 4 ⁇ 0 4 - in the ratio of about 145, 4, 2.5, 1.5, and 1.0 respectively, and a label such as deuterium.
  • the osmolality may be less than about 310 mOsm.
  • the formulations may be administered at a rate of about 3 mg/kg/min, where kg is kg of patient body weight and 3mg is the amount of GNG precursor or MCC in the formulation or at a rate of about 50 mMoles/kg/min, where kg is kg of patient body weight and 50 mM is the amount of GNG precursor or MCC in the formulation.
  • the formulations may have zero or close to zero nutritional content to accommodate a patient that is adequately fed.
  • An initial bolus of label may be given to the patient and the initial bolus labels less than about 1% of the patient's body water and the label may be deuterium.
  • the label may be in a nutritional formulation.
  • the methods and formulations may be used with a patient that is a healthy individual engaged physical activity. They may target a fractional gluconeogenesis range and affect fractional gluconeogenesis.
  • the invention discloses systems and apparatus for carrying out all of the above. It includes systems for estimating the fractional gluconeogenesis of a patient, including: a label administration module, a blood sample module, a glucose analyzer module, a gluconeogenesis calculation module, a total glucose production calculation module, and a fractional gluconeogenesis estimation module. It includes systems for aiding in the estimation of the fractional gluconeogenesis of a patient, including: a glucose molecule analyzer module, a fractional gluconeogenesis calculation module, and a total glucose production calculation module.
  • gluconeogenesis range targeting module includes systems for providing nutritional support to a patient, including: a label administration module, a formulation
  • a blood sample module a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a glucose analyzer module, a
  • gluconeogenesis calculation module includes systems for providing nutritional support to a patient, including a blood sample module, a blood lactate module, and a formulation administration module.
  • the invention discloses systems for targeting a blood lactate range in a patient, including: a blood sample module, a blood lactate module, a formulation administration module, and a lactate range targeting module. It includes systems for targeting a fractional gluconeogenesis range in a patient, including: a blood sample module, a blood lactate module, a formulation administration module, a lactate range targeting module, a label administration module, a second formulation administration module, a blood sample module, a glucose analyzer module, a gluconeogenesis calculation module, a total glucose production calculation module, a fractional gluconeogenesis estimation module, and a gluconeogenesis targeting module.
  • the second formulation administration module and the first second formulation administration module may be the same.
  • the systems may also include a formulation administration module, a body water fraction module, and an absolute rate of gluconeogenesis calculation module that uses absolute rate of glucose production data.
  • the fractional gluconeogenesis calculation module may use abundance of label data for one or more of glucose carbons 1 , 3, 4, 5, 6.
  • the fractional gluconeogenesis calculation module may use abundance of label data for one or more of glucose carbon 2.
  • the data may come from glucose or one or more glucose molecule derivatives or both.
  • the invention also discloses computer products, the products being executable by a processor to perform all of the above methods, systems and apparatus.
  • Figure 1 is a standard chemical representation/ illustration of the molecule glucose, approximate molecular weight (“MW”) 180, in the biologically dominant alpha-D- glucose confirmation.
  • Figure 2 is a standard chemical representation/illustration of the molecule glucose, with all seven hydrogens replaced with deuteriums (as labels).
  • Figure 3 shows the penta-acetate glucose derivative, approximate MW 390, that is part of the mass spectra analysis method, in a preferred embodiment of the invention.
  • Figure 4 shows a fragment of the penta-acetate glucose derivative with all of the hydrogens of interest still on the molecule, approximate MW 331 , as well as the same molecule with different isotopes (MW 332, etc.)
  • Figure 5 shows a fragment of the penta-acetate glucose derivative, approximate MW 271 , as well as the same molecule with different isotopes (MW 272, etc.)
  • Figure 6 shows another fragment of the penta-acetate glucose derivative, approximate MW 169, as well as the same molecule with different isotopes (MW 170, etc.)
  • Figure 7 shows a schematic mass spectrum focusing on the MW 331 and related ions.
  • Figure 8 shows a schematic mass spectrum focusing on the MW 169 and related ions.
  • Figure 9 shows a schematic mass spectrum showing the MW 169, 271 , 331 and related ions.
  • Figure 10 shows an actual GC/MS spectrum of the current invention, showing peaks corresponding to the selected ion monitoring ("SIM”) of the MW 331 and 332 ions, where the intensity of the signal is calculated by integrating the areas under the peaks.
  • SIM selected ion monitoring
  • Figure 1 1 is a flowchart schematically representing GNG methods of the
  • Figure 12 is a schematic diagram of GNG systems of the invention.
  • Figure 13 is a flowchart schematically representing lactate methods of the invention.
  • Figure 14 is a schematic diagram of lactate systems of the invention.
  • Figure 15 is a block diagram of an exemplary computing system that may be utilized to practice aspects of the present disclosure
  • GNG Gluconeogenesis
  • Various embodiments of the present disclosure provide systems and mechanisms for estimating fractional GNG in a patient.
  • the disclosed invention includes systems and methods for determining the nutrition state and needs of the patient also based on the absolute rate of GNG and the rate of glucose appearance, among other measures. It also includes systems and methods for treating patients using nutritive formulations as disclosed.
  • fractional GNG in a patient, and use this to prescribe the rates of parenteral and enteral energy substrate administration to support patient recovery.
  • Some of the expected benefits of this treatment are an increased healing rate and decreased hospitalization time.
  • the results of our invention may make the difference between poor versus good recovery, and in other patients, the difference between life and death.
  • the course of discovery to use fractional GNG as a biomarker of BES and needs for energy substrate nutrition is described here.
  • Inspiration for the invention arose in part from the inventors' cumulative professional experiences in public service, education, and consultation in industry and metabolic research in exercise physiology.
  • metabolic stresses such as the oxygen-limited condition of high altitude, cigarette smoking, and the personal experience of one inventor, Michael Horning ("MAH") observing the metabolic effects of a traumatic brain injury (“TBI”) to a family member served to help the inventors conceive and reduce the invention to practice.
  • MAH Michael Horning
  • TBI traumatic brain injury
  • glycemia is loosely used to mean the state of the body and blood glucose, in particular [glucose].
  • the current invention takes the term and makes it much more precise, by describing underlying mechanisms of glycemic control such as GNG and fractional GNG.
  • the term "tight" glycemic control is sometimes used loosely in the current art to mean a more nuanced approach to control of glucose, but is also not very precise.
  • the current invention provides systems and methods for a sort of "exquisite" glycemic control that is vastly superior at estimating the patient's BES and meeting the patient's nutritional needs.
  • the current art views a sedentary or unconscious patient as resting, and thus not needing any nutritional support beyond that of a resting patient, because he or she is physically inactive.
  • the current art also may view some critical illnesses as
  • GNG involves catabolism of body tissues to support production of glucose, since it is a less favored, inefficient method of glucose production.
  • Glucose is an essential body nutrient and unique fuel for tissues such as brain, nerves, kidneys and red blood cells. To heal and gain strength an ill or injured person needs macronutrient nutrition, in particular, including glucose or glucose precursors.
  • the invention benefits treatment of an ill or injured person by using fractional GNG as the critical biomarker. While the general concept of estimation of fractional GNG by itself is not new, see, for example (3, 14, 20, 26, 27, 73, 74) the invention introduces new and improved systems and methods for such estimation. The invention also further uses these estimates as a highly useful determinant of the balance of BES, e.g., catabolism vs. anabolism and nutritional needs of an ill or injured patient in order to treat, feed and provide nutrition to the patient appropriately. For discussion of the general concept of the general use of biomarkers and measurement of various other aspects of metabolic flux see, for example (28, 65).
  • the invention includes the improvement of continually or dynamically estimating fractional GNG, thus providing an ongoing basis by which to understand the BES of the patient and thus treat the patient, in addition to point measurement of fractional GNG.
  • the invention includes a new metabolic diagnostic test to assess fractional GNG to determine the underlying metabolic and nutritional status, or BES, of a patient.
  • BES metabolic and nutritional status
  • the scientific literature increasingly suggests that such measurements should be made, neither specifies how to specifically interpret such information in the context of the metabolic and nutritive state of the patient, nor how to proceed on this information in terms of formulations and amounts of such formulations (75).
  • the liver, and to a lesser extent the kidneys are the body organs that make new glucose from GNG.
  • the invention also includes using the information derived from the test above to articulate information on the metabolic state and nutritive needs of a patient.
  • fractional GNG is estimated, which alone can be used as a highly useful, even determinative biomarker of BES.
  • the basic principle is to label a portion of the patient's body water and then to estimate the portion of glucose
  • a label such as deuterium can be incorporated onto different positional carbons of glucose depending on whether the glucose was produced by GLY or GNG, such labeling can be used to estimate fractional GNG in the invention.
  • the proportion of body water to be labeled must be large enough to give an accurate measurement of isotopic enrichment in both body water and blood glucose by whatever detection mechanism is used to determine the isotopic enrichments. It should also be highly sensitive so that relatively small blood samples can be taken for comfort and efficacy, and to reduce the cost of isotopic labeling and analyses.
  • that label is deuterium, that is, the hydrogens in the water are the deuterium isotope (written as 2 H or D) and D O is added to body water.
  • This deuterated water (generally commercially available at >98% purity) is generally introduced intravenously to the patient.
  • an amount of deuterated water that approximates 0.3-0.5% of body water is given to the patient as a bolus. This amount is typically estimated by assuming 70% of body weight is water.
  • the labeled water both equilibrates with body water and is
  • the hydrogen atoms on carbon 2 on glucose will be labeled via glucose production in proportion to the labeling of body water, and can be used to validate the % labeling of body water number enriched with deuterium.
  • the fraction of hydrogen atoms enriched by deuterium on C- l of glucose will be equal to that on C-5, but each will have an amount smaller than the enrichment at C-2 due to the combined pathways of GNG and GLY.
  • a blood sample is taken after this initial bolus, and the glucose is extracted using standard methods known in the art via solvents.
  • the glucose is converted to the penta-acetate molecule shown in Figure 2, approximate MW 390, so that this glucose derivative can be detected in a gas chromatograph ("GC") mass spectrometer ("MS").
  • GC gas chromatograph
  • MS mass spectrometer
  • the hydrogen-deuterium atoms on C-2 are removed during ionization so that we can isolate the carbons enriched by deuterium during GNG, thus obtaining the average GNG enrichment.
  • This mass to charge (m/z) ion has a non-labeled molecular mass (“m") of 169 and charge (“z”) of 1. If the ion is enriched with a deuterium at one of the carbons, then its m/z will be 170.
  • the invention can be practiced without chromatography.
  • Sugar measured without a chromatography step to isolate glucose from other blood sugars such as fructose and galactose would still be about 95% glucose, and so a meaningful number for glucose can be obtain without separation.
  • Carbohydrate digestion produces a high percentage of glucose as the fundamental energy source for cell metabolism.
  • Two other forms of sugars, galactose, and fructose are also products of carbohydrate digestion.
  • the liver enzymes convert most of these sugars to glucose, resulting in the 95% number.
  • the ions will be enriched at more than one carbon, and by more than one isotope.
  • endogenous (background) isotopic enrichment of carbon in body substances by ( 13 C) approximates 1.09%.
  • the endogenous (background) deuterium enrichment is very small, approximately 0.015%, and the target D O enrichment in body water is approximately 0.3 to 0.5%, the background deuterium will not meaningfully affect estimation of fractional GNG as described here. It can in any case be corrected for, if desired.
  • the ratio of 170/ 169 ions (further divided by 6, the number of hydrogen atoms on this ionized glucose fragment) divided by body water enrichment will thus yield an abundance value for fractional GNG.
  • the body water enrichment value can either be taken from the bolus to body weight approximation described above (and, in a preferred embodiment, intended to be 0.3 to 0.5%), or estimated from the glucose carbon 2 enrichment via GLY as described in this equation:
  • Fractional GNG ( (abundance 170 / abundance 169) / 6 ) /fraction of body water labeled
  • Figure 2 is a standard chemical representation/ illustration of the molecule glucose, with all seven hydrogens replaced with deuteriums (as labels).
  • Figure 3 shows the penta-acetate glucose derivative, approximate MW 390, that is used in the GC/MS analysis method, in a preferred embodiment of the invention.
  • Figure 4 shows a fragment of the penta-acetate glucose derivative, approximate MW 331 , as well as the same molecule with different isotopes (MW 332, etc.)
  • Figure 5 shows a fragment of the penta-acetate glucose derivative, approximate MW 271 , as well as the same molecule with different isotopes (MW 272, etc.)
  • Figure 6 shows another fragment of the penta-acetate glucose derivative, approximate MW 169, as well as the same molecule with different isotopes (MW 170, etc.)
  • the body water enrichment is taken from observing the abundance of the labeled penta-acetate glucose derivative MW 331.
  • This ion has a non-labeled molecular weight of 331 and charge of 1. Since this ion retains all carbons and hydrogens of the base glucose molecule, it is enriched by both GLY and GNG, at one of the seven hydrogens associated with the six carbons of the glucose, resulting in an ion with molecular weight of 332. Thus the abundance of this molecule represents enrichment by both pathways. Enrichment at carbon 2 is by both pathways, and enrichment at the other carbons is only by GNG.
  • [Ol lOJ Figure 7 shows a schematic mass spectrum focusing on the 331 ion. As stated, relative abundance of the 332 ion (marked with one deuterium) vs. the 331 ion
  • [Ol l lJ Figure 8 shows a schematic mass spectrum focusing on the 271 ion. Since this ion has lost the hydrogen at carbon 2, it cannot be marked by the GLY pathway. The ratio of 272 to 271 thus represents the enrichment due only to GNG. Since the ion may also exist in a configuration where the hydrogen is still present in the molecule, the estimation of enrichment due to GNG may be modified by a correction factor, in one embodiment 1.0/0.9, because about 90% of the molecules exist in the configuration without the hydrogen at carbon 2.
  • Figure 9 shows a schematic mass spectrum focusing on the 169 ion. Since this ion has lost the hydrogen at carbon 2, it cannot be marked by the GLY pathway. The ratio of 170 to 169 represents the enrichment due only to GNG. Since the ion may also exist in a configuration where the hydrogen is still present in the molecule, the estimation of enrichment due to GNG may be modified by a correction factor, in one embodiment 1.0/0.65, because about 65% of the molecules exist in the configuration without the hydrogen at carbon 2.
  • % body water label baseline based on the amount of labeled water introduced into the body compared to body weight and/or total body water estimate (generally body water is assumed to be 70% of body weight) in another embodiment. If the ratio of 332/331 minus 170/ 169 or 272/271 or both differs from this, we can use the average or some other combination of these numbers to establish a baseline for % body water labeled, in another embodiment.
  • FIG. 10 shows an actual Selected Ion Monitoring ("SIM”) GC/MS spectrum of the current invention, showing peaks for selected ions 331 and 332.
  • SIM Selected Ion Monitoring
  • the units of the y-axis are not generally important, as long as the abundance is adequate for good chromatography, since what we care about are intensity/ abundance ratios, and the ratios are dimensionless.
  • the GC/MS used is the Agilent GCMSD 5973.
  • other types of GC/MS devices or other types of mass spectrometers such as liquid chromatographs can be used, provided that the enrichment is sufficient to be accurately detected and the molecules, or derivatives and fragments of the molecules representative of the relevant label or labels can be detected.
  • Other types of mass spectrometers such as, but not limited to, three-dimensional quadrupole ion trap, linear quadrupole ion trap, orbitrap, sector, time-of-flight, Fourier transform ion cyclotron resonance or other detectors.
  • Such detectors can be used alone or in combination (called tandem mass spectroscopy), e.g., triple quadrupole, quadrupole ion trap.
  • ions can occur by a variety of methods and systems, including, but not limited to, electron ionization (“EI”) and chemical ionization (“CI”) used for gases and vapors, electrospray ionization, nanospray ionization, matrix-assisted laser desorption ionization (“MALDI”), inductively coupled plasma (“ICP”), glow discharge, field desorption, fast atom bombardment (“FAB”), thermospray, desorption/ ionization on silicon (“DIOS”), direct analysis in real time (“DART”), atmospheric pressure chemical ionization (“APCI”), secondary ion mass spectrometry (“SIMS”), spark ionization and thermal ionization (“TMS”).
  • EI electron ionization
  • CI chemical ionization
  • MALDI matrix-assisted laser desorption ionization
  • ICP inductively coupled plasma
  • FAB fast atom bombardment
  • DIOS desorption/ ionization on silicon
  • DART direct analysis
  • ionization techniques result in the transformation of the molecule to an ion or multiple fragments of ions.
  • Various chromatographic techniques for example, gas chromatography (“GC”) and liquid chromatography (“LC”) can be combined with the mass spectrometer detectors.
  • GC gas chromatography
  • LC liquid chromatography
  • the interface between liquid phase and gas phase typically uses either nanospray ionization or electrospray ionization.
  • the invention can also be used with single "purpose-built" mass spectrometers. Distinguished from conventional central laboratory mass spectrometers, purpose-built mass spectrometers, typically are small, single biotechnology application, mass spectrometers that use miniaturized molecular traps operating near atmospheric pressure with small versions of pumps, ionizers, detectors and electronics needed. A handheld version can take a small blood sample so that tests such as %GNG can be easily and routinely sampled.
  • the invention can use deuterium oxide (D2O) alone, or D O with either D2- glucose, or [ l- 13 C]glucose tracers administered intravenously upon admission to a hospital intensive care unit ("ICU"), in preoperative preparation or other forms of hospital admittance in order to establish baseline values for glucose Ra, %GNG, and absolute rate of GNG.
  • D2O deuterium oxide
  • ICU hospital intensive care unit
  • estimation of %GNG consists of the intravenous administration of tracer or tracers, a small blood sample (small enough in fact for the diagnostic to be used in infants and children), preparation of sample for analysis and mass spectrometry to determine the mass isotopomer distribution of the incorporation of D O into the product glucose and the deuterium enrichment of the precursor body water.
  • Our relatively easy, fast and cost effective invention can be easily deployed in hospitals and trauma centers throughout the world.
  • %GNG estimates with other analyses (D2O plus either D2-glucose (2 deuteriums at C-6), or [ l- 13 C]glucose (glucose with a carbon 13 at C- l), to yield estimates of glucose Ra and absolute rate of GNG. This would give additional information as to the to determine metabolic and nutritional state of the patient.
  • D2O D2-glucose (2 deuteriums at C-6), or [ l- 13 C]glucose (glucose with a carbon 13 at C- l)
  • fractional GNG glucose being the product of this pathway
  • GNG fractional GNG or %GNG - the terms are used in this invention interchangeably.
  • Our invention for the averaging GNG estimate method is to measure the total deuterium enrichment of all hydrogens of glucose and subtracting the enrichment of deuterium on C- l , C-3, C-4, C-5 and C-6, the difference of which results in calculation of the enrichment of deuterium on C-2 of glucose.
  • the enrichment of deuterium on C-2 is equivalent to the enrichment of deuterium in body water.
  • fractional GNG average ( 1 ,3,4,5, 6,6-H 6 )/( l ,2,3,4,5,6,6-H 7 -1 ,3,4, 5,6,6- H 6 ).
  • the penta-acetate derivative of glucose contains all 6 carbons and 5 acetate functional groups that have replaced the native glucose hydroxyl groups.
  • methane chemical ionization (CI) and electron impact ionization (EI) the first prominent fragments are mass-to-charge (m/z) 331 and the related naturally occurring isotopomers (m/z 332, 333 and 334).
  • This "331 fragment” contains all the carbons of glucose and all the hydrogens of the glucose molecule (i.e., C- l , C-2, C-3, C-4, C-5, C-6 and H- l , H-2, H-3, H-4, H-5, H-6, H-6 [also can be written as 1 ,2,3,4, 5, 6, 6-H7] (7 hydrogens total)).
  • the other ion fragments of interest in the proposed method are m/z 169 and its related naturally occurring isotopomers (m/z 170, 171 , 172).
  • the 169 fragment Similar to the 331 fragment, the 169 fragment also contain all the carbons of glucose, but a different number of related hydrogens (i.e., C- l , C-2, C-3, C-4, C-5, C-6, and H- l , H-3, H-4, H-5, H-6, H-6 [or 1 ,3,4,5,6,6-H6] ) .
  • Aspects of our invention are recognition of the loss of H-2 from the 169 fragment, and inclusion of H-2 in the 331 fragment of the penta-acetate derivative of glucose following the administration of D O and the process of GNG.
  • fractional GNG can be calculated by dividing the "average" 2 H glucose isotopic enrichment (the product) by the body water enrichment following administration of water and D O (the precursor), see, for example, (20, 30, 58). Restated another way, 2 H enrichment on C-2 of a glucose penta-acetate derivative following administration of D 2 O is due to both GNG and GLY.
  • our new and novel method of measuring %GNG depends on determinations of the positional isomers of deuterium labeled glucose during GNG, an assumption that has been verified independently (20, 30). And any one or more of the GNG enriched carbons can be used to arrive at the %GNG estimate.
  • [0127JM+1 ratio m/z (M+l/M); M and M+l represent ion fragments from mass spectrometry
  • the M+l ratio can also be represented as (M+l/Sum (M + (M+l)).
  • M+l ratio 332/(331+332).
  • MPE M+l ratio S am P ie - M+l ratiobackground; sample is blood sample acquired after administration of 2 H20, and background is blood sample acquired upon admittance to hospital and before administration of D2O.
  • M+l ratio (332/331) - M+l ratio (170/169) body 2 H 2 0
  • Total MPE/6 average 2 H enrichment of C-l, C-3, C-4, C-5, and C-6 blood glucose penta-acetate derivative
  • Fractional GNG average 2 H enrichment /body 2 H 2 0
  • the method of invention is comprised of three independent parts.
  • Part 1 comprised of two sub-parts, (1A) administering D2O to an ill or injured patient or to a healthy control in who GNG needs to be measured, and (IB) measure the glucose penta-acetate ion fragmentation patterns by mass spectrometry, as described above.
  • a background blood sample should be drawn and prepared for analysis.
  • the background sample is useful because, depending on a patient's dietary and environmental history, small and variable amounts of 2 H and 13 C isotopomers naturally occur in body water, blood metabolites and other body
  • the desired isotopic enrichment of body water (in one embodiment about 0.3- 0.5%, or adequate for ion intensity comparisons from the utilized method of mass spectrometry) will be adjusted by the constant infusion of D O and verified by the determination of deuterium enrichment on C-2 (as described above using the difference in ion intensities between ion fragments 331 and 169).
  • the determination of body water enrichment can be determined by isotope ratio mass spectrometry (31 , 66) or using an isotopic exchange with acetone method (81). Then, when needed and as frequently as necessary, a small blood sample can be drawn to determine fractional GNG on an ongoing/dynamic basis.
  • the fractional GNG will be controlled, such as within the target range (20-25%) in a preferred embodiment, varied to mimic a normal daily circadian pattern, or varied to yield any particular %GNG ranging from 0 to 100% in other embodiments.
  • GNG the rate of GNG
  • %GNG the rate of GNG
  • %GNG the rate of GNG
  • %GNG the rate of glucose production.
  • % of total glucose production to support the brain approximates 25%, a very high percentage considering the mass of the brain in comparison to the rest of the body.
  • Blood glucose demands increase in injured persons regardless of the site of injury, and the balance of glucose Ra from GLY and GNG varies depending on nutritional state, time and metabolic needs of various body tissues. Paradoxically, following brain injury, cerebral glucose uptake is stunned and diminished, however, the % of cerebral glucose uptake from GNG rises, as has been observed by the inventors and other researchers, in studies to be published in the coming months.
  • %GNG can fluctuate between ⁇ 10% (over fed), to -20-25% (appropriately nourished) to as high as -90% (in undernourished and catabolic patients).
  • Our observations show that %GNG approximates 70% for TBI persons in the ICU, as has been observed by the inventors and other researchers, in studies to be published in the coming months.
  • %GNG is a variable that can have physiological range of 0 to 100%. Based on our work as well as that of others, the stated target range of 20-25% in healthy post-absorptive individuals, is a biomarker for adequate nutrient delivery in an ill or injured patient or other individual incapable of taking adequate macronutrient nutrition, as defined by the Harris-Benedict (32) or Institute of Medicine equations (8, 51). In a preferred embodiment of the invention, nutrition is provided so that %GNG is between about 15 and 30%. In another preferred embodiment of the invention %GNG of about 20-25% is aimed for based on studies on healthy young individuals 3-4 hours after having eaten (3, 24, 26, 27, 58, 73).
  • Part 2 articulates the metabolic and nutritive state, also known as body energy state (76) of the patient.
  • body energy state (76) the acquisition of the mass isotopomer distribution of the deuterium and hydrogen content in the body water and the glucose, taking into consideration the natural occurrence of isotopes of carbon and other atoms with naturally occurring isotopes, consists of selective ion monitoring ("SIM") of the mass to charge ratio (m/z) of the ions of interests coupled with an integration of the SIM to deduce the response factor associated with the abundance of the ions of interests as they relate to the precursor and product relationship.
  • SIM selective ion monitoring
  • the invention also includes a method and system to compare the precursor and product relationship based on the patient's baseline measurement and the daily (or multiple daily) measurements taken from the patient.
  • the invention in a preferred embodiment, has a database that informs the basis from which the nutritional status was evaluated and the prescription of nutritional support was determined. With the additional process of part 1 , the database will contain variables for the relevant ions (e.g., 331 , 332, 272, 271 , 169, 170) to calculate fractional GNG and body water
  • the system will contain non-identifiable data on patients, the severity of injury on entry into the study, the initial %GNG, the enteral and parenteral nutrition provided, and patient outcomes.
  • a typical, general purpose computer system suitable for implementing the present invention includes any number of processors that are coupled to memory devices including primary storage devices such as a read only memory, random access memory and hard drives. Any one of many data and database architectures can be used to store and retrieve methods, protocols and recommendation, to store data, and to communicate with server side assistance through the Internet and other networks.
  • [0148JA hardware system may be specially constructed for the required purposes, or it may be a general-purpose computer, such as a server computer or a mainframe computer, selectively activated or configured by a computer program stored in the computer.
  • a general-purpose computer such as a server computer or a mainframe computer, selectively activated or configured by a computer program stored in the computer.
  • the processes presented above are not inherently related to any particular computer or other computing apparatus.
  • various general-purpose computers may be used with programs written in accordance with the teachings herein, or, alternatively, it may be more convenient to construct a more specialized computer system to perform the required operations.
  • a general-purpose computer system suitable for carrying out the processing in accordance with one embodiment of the present invention can be a server computer, a client computer, or a mainframe computer.
  • Other computer system architectures and configurations can be used, made up of various subsystems described below, includes one or more microprocessors (or central processing units). Using instructions retrieved from memory, the microprocessor controls the reception and manipulation of input data, and the output and display of data on output devices.
  • Part 3 relates to nutritive methods, formulations and amounts.
  • the attending physician shall administer the level of nutritive support to administer to each patient to normalize the %GNG. Further, the attending physician or other health care professional shall utilize information from continual determinations of GNG and nutrient delivery following application of parts 1 and 2 of the invention for each patient as they recover or as conditions change.
  • the invention will prescribe feeding protocols for the patient, as follows, based on general nutritional concepts described in (8, 51).
  • a preferred form of treatment will consist of the intravenous infusion of the gluconeogenic precursor, including any of the following in combination or alone: L-(+)- lactate salts, other lactate compounds, L-(+)-pyruvate salts, other pyruvate compounds, L-(+)-lactate alone, lactate plus other amendments included in lactate, pyruvate and similar nutritional molecules are herein referred to as monocarboxylate compounds ("MCC").
  • MCC monocarboxylate compounds
  • GNG precursors include many MCCs, such as those listed herein, as well as other compounds, such as some amino acids (e.g., alanine) and glycerol compounds.
  • nutritive formulations are referred herein as cocktails, infusions, formulations, MCC cocktails and GNG precursor cocktails.
  • rate of MCC infusion would range from high ( 13) to low (13) as governed by the individually measured %GNG and glucose appearance rates:
  • the MCC cocktail would be sodium-L-(+) -Lactate prepared by titrating L-(+)-Lactic acid with NaOH (24, 52, 55-57). Briefly, the MCC infusion cocktail is prepared by mixing 30% L-(+)-lactic acid solution (e.g., Sigma) in 2 N NaOH to pH 4.8.
  • L-(+)-lactic acid solution e.g., Sigma
  • the invention specifies an initial infusion rate would deliver 1 1-50 (micro Moles per kg of body weight per minute) mMoles/kg/min, with maintenance infusion rate targeting blood lactate concentration of 3.5 - 4.5 mM. Higher blood lactate levels (6 mM) have been seen without ill effects (57, 71). Consistent with section methods described above, assuming a formula weight of 1 12 mg/mMol for sodium lactate, an infusion rate of 1 1 mMoles/kg/min would deliver the mass equivalent of 1.0 mg/kg/min of glucose, an infusion rate of 23 mMoles/kg/min of sodium lactate MCC would deliver the mass equivalent of 3 mg/kg/min glucose, whereas an infusion rate of 50
  • the MCC is prepared from highest purity materials, is pathogen free, certified for human pharmaceutical use and is delivered into a large central vein, but peripheral vein can be used if administered with physiological saline to minimize osmolality and pH effects at the infusion site that might provoke phlebitis of hemolysis.
  • the starting MCC infusion rate is approximately 3
  • the invention provides for adjusting the nutrition, including MCC infusion rates, such that a target %GNG is achieved.
  • MCC infusion rates such that a target %GNG is achieved.
  • results of studies of the extent of gluconeogenesis in humans might seem quite variable; however, if results are viewed from the context of subject time since last eating, then a clear pattern emerges: GNG is suppressed as nutrients enter the gut, portal and circulation (e.g., 0- 15% of glucose Ra), and 20-25% of glucose Ra 3-4 hr after a mixed, CHO (carbohydrate) containing meal, and the percentages rises continuously thereafter (74).
  • Procedure A An alternative and also preferred form of treatment will involve Procedure A plus either (B l) enteral nutrition via nasal gastric or nasal jejunal tube, or parenteral nutrition (B2) via intravenous catheter. If these, Method B l is useful because nutrients will enter the stomach and reach intestines, portal circulation and liver, thereby eliciting physiologically appropriate and anabolic local intestinal and long neural endocrine reflexes as well as general endocrine responses with signals reaching the liver, pancreas, muscles, heart, adipose, and brain including hypothalamus regarding the presence of appropriate nutritive energy support (79).
  • TEE 1864-9.72 x age [yr] + PAL x ( 14.2 x weight [kg] + 503 x height [m])
  • Another embodiment of the invention relies on robust, scientifically determined underpinnings of the metabolic and GNG responses to trauma, including neurotrauma, as has been observed by the inventors and other researchers, in studies to be published in the coming months, and is to be regarded as an emergency procedure when isotopes and analytical equipment are unavailable and the patient needs to be sustained until relocation to an appropriately equipped facility.
  • Another embodiment of the invention also relies on robust, scientifically determined underpinnings of the metabolic and GNG responses to trauma and is to be regarded as an emergency procedure when isotopes, analytical equipment and MCCs are unavailable and the patient needs to be sustained until relocation to an appropriately equipped facility.
  • Such locations could include, for example, a battlefield or a rural setting.
  • D le If enteral or parenteral support is unavailable, the clinician shall commence intravascular infusion of D-Glucose at the rate of 3 mg/kg/min which is the empirically derived best estimate of body glucose flux following a TBI or other injury, illness or situation, as has been observed by the inventors and other researchers, in studies to be published in the coming months.
  • This elevated value of glucose flux that occurs after TBI or other injury, illness or situation, is indicative of a "hypermetabolic" state would be in contrast to the depression in glucose flux as might occur in a "hypometabolic" state, such as advanced ageing (see below, vide infra).
  • nutritive support treatment targets are %GNG 20- 25%.
  • plasma [glucose] is targeted as 5-7mM.
  • plasma [lactate] is targeted as 3-4mM.
  • an MCC that can be comprised of one, or combinations of the following: sodium L-(+)-lactate, arginyl lactate, glycerol, glycerol tri-lactate, sodium L-(+)-pyruvate, arginyl pyruvate, glycerol tri-pyruvate, glycerol tri-acetate, b-OH-butyrate or acetoacetate [in which all monocarboxylate enantiomers are L-(+)- enantiomers], or mixtures thereof in which the relative amount of any single constituent could range from 0- 100%.
  • a MCC cocktail could include Ca ++ , Mg ++ , and K + -salts of lactate, pyruvate, alanine, b-OH-butyrate, acetoacetate, etc., as all are salts of monocarboxylic acids.
  • sodium ion (Na + ) is the main cation in plasma, normally 145mM, other cations are far less abundant in plasma.
  • K + , Ca ++ , and Mg ++ are, respectively, 4, 2.5 and 1.5 mM.
  • inorganic lactate salts comprised of Na + , K + , Ca ++ , and Mg ++ would be given in the ratio of 145, 4, 2.5, and 1.5.
  • the main anion would be lactate, but phosphates (P0 4 3 - ), hydrogen phosphate (HP0 4 2 ) and dihydrogen phosphate ( ⁇ 2 ⁇ ⁇ ) , in the amount of 1.0 mEq would be provided as well.
  • this particular embodiment of MCC could be termed "Sanguisal" from the Latin words for blood (sanguis) and salt (53).
  • the provision of sodium and other cations as a means to deliver lactate anions in an MCC has the advantage of reducing brain swelling following TBI, as has been observed by the inventors and other researchers, in studies to be published in the coming months and ( 15) as well as providing nutritive support to intensive care patients following trauma (70).
  • Sanguisal-P will involve the use of pyruvate (P) as the major anion, while at the same time maintaining the above-stated levels of cations ⁇ Na + , K + , Ca ++ , Mg ++ , and H PO4" as are present in the plasma of healthy individuals: 145, 4, 2.5, 1.5, and 1.0 mEq/1 ⁇ .
  • pyruvate is the precursor to lactate in glycolysis.
  • pyruvate is an oxidizable fuel and GNG precursor whose metabolism may affect cell redox status if converted to lactate. Although typically present in 1 / 10 or lesser concentration
  • pyruvate compared to lactate, pyruvate has been introduced into the systemic circulation of large mammals in which the circulation has been interrupted to mimic cardiac arrest (61-63, 68). In such cases 100% pyruvate infusion raises the circulating pyruvate level, but more so, the circulating lactate level achieving a circulating L/P of 2-3 (69). None the less, because of its chemical structure, pyruvate has the advantage over lactate of serving as an antioxidant in the myocardium subjected to reperfusion injury, and, by extension exogenous pyruvate my also serve to scavenge free radicals in the brain after blood flow is interrupted.
  • the invention is comprised of a three-part process to assess the metabolic status and deliver macronutrient energy to an ill or injured human or other mammal.
  • the first part is to estimate the %GNG, the favored method is to utilize deuterium oxide (D2O) alone, or D O with either D2-glucose, or [ l- 13 C]glucose tracers administered
  • One advantage of the new method is that the tracer needs to be given once that will suffice for measurements of GNG to be made daily for several days and a constant infusion can be started to offset the dilution of the enrichment of the deuterium oxide caused by intake of fluids.
  • the former method (glucose recycling) requires using D2-glucose (that does not involve carbon recycling, and a 13 C-glucose tracer (e.g., [ l- 13 C]glucose) in which the carbon recycles (26, 27).
  • %GNG ( 100) Ra Glucose (from 13 C-glucose) - Ra Glucose (from D2-glucose)/Ra Glucose (from D2-Glucose).
  • tracers will need to be given continuously over days, perhaps leading to weeks, and that assumptions need to be made over the extent of carbon isotope dilution in the Krebs (tricarboxylic acid) Cycle (37, 38).
  • Another method also uses deuterium oxide and measures the deuterium incorporation on glucose carbons using the mass isotopomer analysis technique with the aldonitrile penta- acetate and methyloxime-trimethylsilyl derivatives (42).
  • Another alternative method also uses deuterium oxide but measures the enrichment at carbon 2, 5, and 6 of glucose using the HMT (hexamethylebetetramine) derivative. Disadvantages of this method are the complexity in preparing the derivative (44, 45).
  • fractional GNG D2O, also called deuterium oxide or heavy water, either alone or in combination with [6,6- 2 H]glucose (i.e., DD- glucose or D2-glucose) or [ l- 13 C]glucose) (20), is administered intravenously.
  • D2O also called deuterium oxide or heavy water
  • a blood sample can be obtained, and the mass isotopomer distribution in the blood sugar glucose produced from the heavy water precursor can be analyzed to determine the percentage contribution of gluconeogenesis (%GNG) to the total rate of hepatic plus renal glucose production, alternatively termed glucose appearance (Ra glucose) that can be determined from the isotopic enrichment ("IE”) of D2-glucose in blood.
  • %GNG percentage contribution of gluconeogenesis
  • Ra glucose isotopic enrichment
  • IE isotopic enrichment
  • the major GNG precursor is the monocarboxylate, 2-hydroxy-propionate (also known as lactate) (3, 40, 54), which is also a major energy substrate for most body tissues (5-7), including the brain (28, 33, 64).
  • lactate also known as lactate
  • the salts of other monocarboxylic acids are also gluconeogenic precursors; these include: pyruvate, acetate, acetoacetate, b-hydroxybutyrate, and related compounds, see below.
  • monocarboxylic acids lactic, pyruvic, acetic, tarry droxy butyric, acetoacetic acids, etc.
  • monocarboxylate anions lactate, pyruvate, acetate
  • the fractional GNG is used to determine nutritive support rate to achieve preferred glucose Ra and fractional GNG.
  • an injured patient may have an increased metabolic rate (hypermetabolic) and thus need both glucose and GNG precursor support.
  • an aging or chronically ill patient may have a depressed whole body metabolic rate (hypometabolic), but still an elevated need for GNG precursors without glucose support.
  • [glucose] which is commonly measured, but without a clear picture of the fractional GNG rate (our biomarker for the metabolic and nutritive state of the patient)
  • a clinician may not recognize that the patient is in a catabolic state and is degrading essential body stores to provide the precursors and energy for GNG.
  • a clinician might induce a nutritional state that renders the patient overfed by administering too much nutrition because a lack of knowledge of the underlying metabolic and nutritional status of the individual patient.
  • An overfed patient can result in significant metabolic stress and may result in complications including prolonged mechanical ventilation, infection risk, delayed hospital discharge and even increased morbidity (29, 47).
  • a clinician may be unaware of the body's attempt to supply glucose from gluconeogenesis, and, in fact, the clinician may inadvertently act to suppress GNG (78).
  • TBI also known as intracranial injury
  • TBI also known as intracranial injury
  • the mechanism of injury produces two, or more lesions, one a laceration or contusion at the site of impact or cranial penetration, and the other a contralateral contusion injury if the force of impact is sufficient to accelerate the brain such that it forcibly contacts the cranium at a vector directed by the initial impact.
  • TBI can be classified based on severity, mechanism (closed or penetrating head injury), or other features, e.g., occurring in a specific location or over a widespread area (15, 28).
  • TBI Head injury usually refers to TBI, but is a broader category because it can involve damage to structures other than the brain, such as the scalp and skull (15). TBI is a major cause of death and disability worldwide, especially in children and young adults and the elderly. Causes include falls, vehicle accidents, and violence.
  • the description includes examples of patient treatment following trauma and chronic illness.
  • the invention includes, methods for managing those extreme and other cases and instances when assessment of BES, diagnosis and treatment are appropriate. Such examples include, but are not limited to assessing BES of patients or others before and after surgery, before and after drug treatment or dietary intervention, or any situation in which knowing, or standardizing BES is essential for determining outcome of any treatment, or establishing the effect of said treatment on humans or other
  • [0204JGNG is part of normal physiology that includes the "fight-and-flight" response to emergency situations that is well-known in the art, see for example the classic work of Selye (67), and the reference books by Cannon, W. B. "Thefulness of the Body” ( 17) and Brooks ( 12)).
  • gluconeogenesis works to maintain blood glucose concentration, or glycemia, in the normal range in the early morning hours after the previous evening's meal has been digested and nutrients cleared from the blood, and when the maintenance of glycemia depends on GNG (54) .
  • GNG GNG
  • Commonly stated examples given to illustrate importance of the fight and flight response are evolutionary in nature, such as the need to flee predators, or catch large game animals.
  • GNG glycogen
  • patient often refers to an individual (human, other mammal or even other animals) suffering from injury or chronic disease. It can also refer to acutely or chronically stressed individuals such as premature infants, the chronically
  • fractional GNG has already been measured in persons suffering many of the illnesses listed above; however, to date none have recognized that the nutritional needs of ill and injured patients could be met by targeting a constant range.
  • treatment of an ill or injured individual would involve negative feedback control of enteral nutrition and MCC infusion: response to high %GNG would be increasing enteral nutrition and MCC infusion, whereas low %GNG would mean over nutrition and the need to reduce feeding rate.
  • a range of near 25% is generally an appropriately fed state, 3-4 hr after a balanced, CHO-containing meal.
  • a low level of fractional GNG, around 10% would be measured soon after they consumed a balanced, CHO-containing meal.
  • a low fractional GNG of around 10% in a comatose individual, such as a TBI patient in an ICU a GNG of 10% is unlikely, as has been observed by the inventors and other researchers, in studies to be published in the coming months, but would be indicative of over feeding and the need to reduce enteral feeding and MCC infusion until %GNG is in the 20-25% range, thus avoiding some of the consequences as described above.
  • More typical of a TBI patient in the ICU would be %GNG > 40%, thus requiring increased provision of enteral nutrition and vascular MCC infusion.
  • the approach should be to maintain glycemia with both enteral nutrition and MCC infusion, the latter being important to supply cerebral nutrition and electrolytes to reduce cerebral swelling and minimizing hyperglycemia from dextrose.
  • fractional GNG of 20-25% is aimed for, in another 15-35%.
  • fractional GNG is the key biomarker of the pathophysiology related to critical illness.
  • fractional GNG also, none have used knowledge of fractional GNG to assess patient nutrient needs. We have devised such methods for intravenous, oral or gastric nutrient delivery to patients.
  • the invention also includes methods for managing those extreme and other cases and instances when assessment of BES, diagnosis and treatment are appropriate. Such examples include, but are not limited to assessing BES of patients or others before and after surgery, before and after drug treatment or dietary intervention, or any situation in which knowing, or standardizing BES is essential for determining outcome of any treatment, or establishing the effect of said treatment on humans or other mammals.
  • the present invention of being able to determine, and nourish individuals to the point of controlling GNG and establishing a stable background in which to evaluate effectiveness of a new drug, the patient treatments could be optimized. Also, costs associated with testing for the effectiveness of new drugs could be minimized.
  • the application of %GNG may also improve dose response and efficacy for already established drugs or for new uses for drugs already on the market.
  • the commonly used drug Decadron (Dexamethasone) may have a new application in post-surgery applications for inflammation.
  • Decadron will affect the metabolic function of the patient. This augmented metabolic function might cause the patient to become catabolic simply from the administration of the drug and thus obviate the desired anti-inflammation characteristics of the drug by causing an undesirable side effect. If this action were to happen, the application for the drug might be interpreted to cause the patient to have a poor outcome. However, the outcome might be enhanced by proper nourishment using %GNG as a diagnostic. Under an appropriately nourished state, the administration of Decadron could minimize inflammation, leading to desired affect of administration of the drug and potentially a better overall outcome for the patient.
  • %GNG Fractional gluconeogenesis
  • gluconeogenesis have been subjects of investigation (43, 77). Gluconeogenesis has been reported to be established 4-6 hr after birth in full-term children (43), and
  • gluconeogenesis does respond to the availability nutritive support (77). Extremely low birth weight pre-term infants do present abnormalities in the ability to regulate GNG in response to nutrient supply ( 19), but nutritive support is none-the-less essential to the survival in such infants.
  • formulation could include 0- 100% propionate.
  • the MCC cocktail would be sodium-L-(+) -Lactate prepared by titrating L-(+)-Lactic acid with NaOH. The following describe such procedures:(24, 52, 55-57). Briefly, the MCC infusion cocktail is prepared by mixing concentrated (30 - 88%) L-(+)-lactic acid solution (e.g., Sigma-Aldrich or PCCA) in 2 N NaOH to pH 4.8. In the example provided, the starting point is a 30% stock lactic acid solution: 300 g 30% lactic acid stock solution is titrated with 133.3 g 2N NaOH and diluted to 1 ,000 ml with water.
  • L-(+)-lactic acid solution e.g., Sigma-Aldrich or PCCA
  • the MCC is prepared from highest purity materials, is pathogen free, certified for human pharmaceutical use and is delivered into a large central vein, but peripheral vein can be used if administered with physiological saline to minimize osmolality and pH effects at the infusion site that might provoke phlebitis of hemolysis.
  • the MCC cocktail would be sodium-L-(+)- Lactate prepared from the dry, powdered salt in deionized water to the concentration intended [e.g., for an isosmotic solution: 154 mM lactate (plus 154 mM Na + ) total osmolarity 308 mOsm/1], and infused in the above-stated amounts to raise arterial pressure
  • the basic sodium-L-(+)-Lactate cocktail would be amended to include other lactate salts as exist in the plasma of healthy humans.
  • Sodium ion (Na + ) is the main cation in plasma, normally 145 mM, and values for K + , Ca ++ , and Mg ++ are, respectively, 4, 2.5 and 1.5 mM.
  • a mixture of inorganic lactate salts comprised of Na + -, K + -, Ca ++ -, and Mg ++ -lactate would be combined in the ratio of 144, 4, 2.5, and 1.5.
  • the main anion would be lactate, but phosphates are important ions in energy metabolism and would be added in the form of 1 mM NaH 2 P0 4 -. Because Na + , K + , Ca ++ , Mg ++ , and H 2 P0 4 - are present in the plasma of healthy individuals at levels of 145, 4, 2.5, 1.5, and 1.0 milliequivalent per liter (mEq/1) (53).
  • This particular embodiment of MCC could be termed "Sanguisal" from the Latin words for blood (sanguis) and salt.
  • the provision of sodium and other cations as a means to deliver lactate anions in an MCC has the advantage of reducing brain swelling following TBI (15) as well as providing nutritive support to intensive care patients following trauma (70).
  • Sanguisal-P will involve the use of pyruvate (P) as the major anion, while at the same time maintaining the above-stated levels of cations ⁇ Na + , K + , Ca ++ , Mg ++ , and 3 ⁇ 4 ⁇ 0 4 - as are present in the plasma of healthy individuals: 145, 4, 2.5, 1.5, and 1.0 mEq/1 ⁇ .
  • pyruvate is the precursor to lactate in glycolysis.
  • pyruvate is an oxidizable fuel and GNG precursor whose metabolism may affect cell redox status if converted to lactate.
  • pyruvate possesses antioxidant properties (48). Although typically present in 1 / 10 or lesser concentration compared to lactate, pyruvate has been introduced into the systemic circulation of large mammals in which the circulation has been interrupted to mimic cardiac arrest (61-63, 68). In such cases 100% pyruvate infusion raises the circulating pyruvate level, but more so, the circulating lactate level achieving a circulating L/P of 2-3. None the less, because of its chemical structure, pyruvate has the advantage over lactate of serving as an antioxidant in the myocardium subjected to reperfusion injury, and, by extension exogenous pyruvate my also serve to scavenge free radicals in the brain after blood flow is interrupted.
  • Sanguisal-P in contrast to the Sanguisal-L form, is that in circulation pyruvate is rapidly converted to lactate due to the effects of lactate dehydrogenase in red blood cells and the lung parenchyma (41) .
  • the optimal site of Sanguisal-P infusion would be in the carotid artery or ascending aorta.
  • the clinician would have the opportunity to affect redox status in an injured brain.
  • Sanguisal-P would be sodium-L-(+)-Pyruvate prepared by titrating L-(+)-Pyruvic acid with NaOH as described above for lactate (24, 52, 55-57) .
  • the initial Na + -pyruvate infusion rate would deliver 1 1 -50 (micro Moles) mMoles/kg/min, with maintenance infusion rate targeting blood lactate concentration of 3.5 - 4.5 mM, although higher levels (6 mM) have been used without ill effects (57, 71) .
  • infusion rate of 1 1 mMoles/kg/min of sodium pyruvate MCC would deliver the mass equivalent of 1.0 mg/kg/min of glucose
  • an infusion rate of 23 mMoles/kg/min would deliver the mass equivalent of 3 mg/kg/min glucose
  • an infusion rate of 50 mMoles/kg/min of sodium pyruvate MCC would deliver the mass equivalent of 4.5 mg/kg/min of glucose.
  • the Na + -pyruvate MCC is prepared from highest purity materials, is pathogen free, certified for human pharmaceutical use and is delivered into a large central vein, but peripheral vein can be used if administered with physiological saline to minimize osmolality and pH effects at the infusion site that might provoke phlebitis of hemolysis.
  • the MCC cocktail would be sodium-L-(+)- Pyruvate prepared from the dry, powdered salt in deionized water to the concentration intended, and infused in the above-stated amounts to raise arterial [lactate] to the intended levels.
  • formulations such as Sanguisal P and Sanguisal L-P mixtures should be anhydrous. Pure sterile water can be added immediately before delivery to avoid pyruvate
  • the basic sodium-L-(+)-Pyruvate cocktail would be amended to include other pyruvate salts as exist in the plasma of healthy humans.
  • Sodium ion (Na + ) is the main cation in plasma, normally 145mM, and values for K + , Ca ++ , and Mg ++ are, respectively, 4, 2.5 and 1.5 mM.
  • a mixture of inorganic lactate salts comprised of Na + -, K + -, Ca ++ -, and Mg ++ -lactate would be combined in the ratio of 144, 4, 2.5, and 1.5.
  • the main anion would be pyruvate, but phosphates are important ions in energy metabolism and could be added in the form of 1 mM NaH 2 P0 4 -. Because Na + , K + , Ca ++ , Mg ++ , and H 2 P0 4 - are present in the plasma of healthy individuals at levels of 145, 4, 2.5, 1.5, and 1.0 miUiequivalent per liter (mEq/1, this particular embodiment of MCC could be termed "Sanguisal" from the Latin words for blood (sanguis) and salt (53); in this case Sanguisal- P (for pyruvate).
  • the invention can also provides nutritive support to intensive care unit patients following trauma (70), and acting as a reactive oxygen species (“ROS”) scavenger (48).
  • ROS reactive oxygen species
  • Sanguisal-P would be prepared from the dry, powdered pyruvate salts (Na + , K + , Ca ++ , Mg ++ , and H 2 P0 4 ) in the ratios of 145: 4: 2.5: 1.5: 1.0 in sterile deionized water to an anion concentration of 154 miUiequivalent per liter (mEq/1), and infused in the above-stated amounts to raise arterial [pyruvate] to 1-2 mM and an arterial [lactate] in the intended range.
  • mEq/1 miUiequivalent per liter
  • Sanguisal (S) mixes of 100% S-Pyruvate to 100% S-Lactate may be used to provide nutritive support to the injured brain and other injured or non-injured tissues, provide a gluconeogenic precursor, and scavenge ROS in all tissues perfused.
  • lactate is the preferred monocarboxylate compound (MCC) in nature: the L/P in arterial blood of healthy individuals is minimally 10, and rises more than an order of magnitude in normal physiology.
  • MCC monocarboxylate compound
  • pyruvate is rapidly converted to lactate in the blood by the action of lactic dehydrogenase in erythrocytes (RBCs) in the blood (69) and the lung parenchyma (41), and lactate, not pyruvate, it the major fuel source and GNG precursor (see above).
  • Sanguisal-L and -P are inorganic salt-based means to deliver nutritive support. However, it is possible to deliver lactate and other nutritive
  • Arginyl lactate (US Patent 5,420, 107) has been extensively used as an (enteral) amendment to sports drinks to provide energy and blood buffering (1 , 25). Arginyl lactate is formed by the
  • LNACE lactate thiolester formed from the combination of lactate and N- acetylcysteine
  • GTL glycerol tri-lactate
  • Glycerol tri- lactate is formed by the esterification of glycerol by lactic acid by means of organic or enzymatically catalyzed processes (see, for example, US Patent 6,743,821). These individual units rapidly dissociate because of the lipases and esterases in human plasma.
  • the components of GTL glycerol and lactate
  • Glycerol has been used as a plasma expander (76) and gluconeogenic precursor (73).
  • GTL is preferred over sodium- and other inorganic salts of lactate because more lactate is carried, no sodium load is incurred, and because the glycerol carrier is efficacious.
  • GTA glycerol tri-acetate
  • acetin glycerol tri-acetate
  • Acetate is another body, although not brain, fuel energy source.
  • State of the art is to provide parenteral nutritive support to patients using 5% dextrose (D5W, glucose in water, vide supra). Because glucose (dextrose) has a molecular weight of 180, osmolality of D5W is 278 mM, which in the low range of normal plasma osmolality (275-310 mEq/1). Even though the glucose concentration in D5W is 50 times greater than homeostatic in plasma, in terms of its isosmotic effect with glucose alone being the only solute, D5W is isosmotic. Mixing equal isosmotic solutions such as equal volumes of 154 mM Sanguisal-L and D5W glucose will produce an osmolality in the high end of the normal range. As noted earlier, this slightly elevated osmolality because of sodium content will draw fluid from tissues into the vascular compartment, thus mitigating swelling due to injury (15).
  • %GNG is unknown, with the assumption that blood glucose can be monitored in real time, a clinician can provide parenteral and enteral nutrition as described above.
  • a clinician may moderate the course of providing lactate- and, or, pyruvate- based MCCs, and instead supplement the patient with D5W, in extreme hypoglycemia, D 10W (5 mM glucose (dextrose)).
  • D2O Another preferred form of D2O could be to make common intravenous saline solutions 0.3 to 0.5 % D2O as the majority of the exogenous fluids delivered to an ill or injured patient comes form the intravenous ("i.v.") saline solutions routinely used in the hospital.
  • i.v. intravenous
  • the exogenous fluid load can be controlled by the clinician through use of the common i.v. saline solution, then the enrichment of body water by deuterium can also be controlled and therefore the measurement of %GNG can be made for the duration of the stay at the hospital as frequently as required by the attending clinician. For example, if 100% of the exogenous solution come from the i.v. saline solution and the i.v.
  • the i.v. solution will have approximately 0.3 to 0.5 g of D2O added. If enteral feeding, for example, contributes 25% of the exogenous fluids, then the D2O saline solution could contain 25% more D2O to accommodate for the increased ingestion of exogenous fluids. Therefore the saline solution would now contain approximately 0.375 to 0.625 g D2O. [0260]Nutritional Support and Lactate Range Targets Without, or In Advance of, BES/% GNG Measurements
  • the general approach of this embodiment of the invention is to target a range or ranges of blood lactate concentrations, [lactate] using formulations containing sodium- lactate, lactate esters and polymers, and/or other MCC and GNG precursors. This helps ensure adequate energy supply and limited catabolism of the patient far better than simply targeting a [glucose] range as is done in the current art.
  • the [lactate] can be measured as easily as [glucose] can be (in a drop of blood), and so can be taken such at the site of an incident such as a sports venue, battlefield, emergency vehicle, as well as hospital emergency room or ICU.
  • an incident such as a sports venue, battlefield, emergency vehicle, as well as hospital emergency room or ICU.
  • [glucose] provides no information on the BES of a patient unless it falls well outside of normal physiological range. At this point, dire hypoglycemia or hyperglycemia conditions exist for the patient.
  • [glucose] measurements also do not provide actionable data on what nutritional action to take - by contrast, [lactate] does provide such actionable data, even if it does not provide true insight into the BES of a patient.
  • lactate is by far most important ( 1 1 , 12, 24, 54, 1 13). As part of the body's protective fight-and-flight mechanism, blood lactate generally rises, and this rise acts to provide lactate as a GNG precursor and fuel for injured and other tissues. However, depending on the manner and time of injury and the nutritional state of the patient, the rise in lactate may be inadequate to meet patient needs especially as the body energy stores are depleted.
  • Lactate (24, 52, 55-57, 104) and other MCC or GNG precursor supplementation are of great benefit to the patient not only because it is a fuel energy source for the body in general (3, 5-7, 55, 56, 104, 1 12, 1 16, 1 17), but because it is especially important for tissues and organs such as the brain (33, 105, 1 15, 1 18).
  • the brain swelling that accompanies injury can be mitigated by providing sodium ions using lactate as the carrier vehicle (108).
  • Lactate supplementation whether given orally or intravenously, is known to provide fuel to the working muscles of athletes and others engaged in vigorous physical activity. Oral or intravenous administration of lactate is safe and has no apparent side effects except mild alkalosis. This can possibly being an actual advantage to the ill or injured when acidosis is a problem ( 101) as it is in high- intensity exercise and hypermetabolic patients.
  • the invention provides for various methods and systems for assessing BES and providing nutritive support.
  • the interim between onset of injury or sudden illness and the assessment of BES by %GNG can be a period of nutritionally unsupported risk to the patient without immediate supplementation.
  • the benefits of lactate supplementation to athletes are here adapted for use with ill, injured and nutritionally compromised patients.
  • the inventors now describe targeting a range of [lactate] concentration as both an interim and even long-term method for providing for the nutritional needs of the patient.
  • Infusion of lactate or other MCC or GNG precursor can also be provided even before measurement of [lactate], to be on the safe side in terms of providing adequate nutrition to the patient.
  • [glucose] is generally not affected by supplementation by lactate or other MCC or GNG precursors because of the preferential use of lactate as a fuel energy source and autoregulation of hepatic glucose production ("HGP"). Because HGP is tightly controlled, elevated availability of GNG precursors (such as the MCC, lactate) will increase the component of HGP from GNG, and decrease the contribution of GLY. Thus [glucose] is not only generally less useful than [lactate] as a indication of nutritional needs, it is especially limited with respect to the nutritional protocols of the current invention.
  • the liver uses exogenous as well as endogenous reserves of lactate, pyruvate, glycerol, alanine and other gluconeogenic amino acids to produce glucose via GNG.
  • This catabolism of body tissues to support GNG has both short- and long-term negative consequences including body wasting.
  • Providing lactate or other MCC or GNG precursors (that quickly become lactate) to an ill or injured patient will mitigate catabolism of body tissues.
  • a normal [glucose] may belie metabolic stresses within a body working very hard to maintain glycemia in the normal range and thus is depleting body energy stores and tissues.
  • lactate The biomarker blood [lactate] is well known in the art and simple to assess from a blood test used to determine the level of metabolic stress in athletes and others engaged in vigorous physical exercise. Recent papers show that in contrast to classical thinking, providing lactate orally or intravenously can enhance an athlete's physiological status and performance. Intravenously provided lactate supports blood glucose homeostasis in at least two major, related ways. Lactate is a GNG precursor and lactate is itself a major fuel source (4, 104, 1 12, 1 16, 1 17) surpassing glucose in magnitude of both
  • a lactate clamp is a glucose clamp, in that a particular [lactate[ or range is targeted, as is done in the art with [glucose] and glucose.
  • a lactate clamp with an infusion of a sodium lactate or other MCC or GNG precursor cocktail that raises blood [lactate] to 4 mM, or other target blood [lactate] or range.
  • infusion of sodium lactate or other MCC or GNG precursor cocktail is followed by frequent monitoring of blood [lactate], with increases or decreases in infusion rate as the target blood [lactate] is achieved and maintained.
  • a LC is employed in exercising healthy young men (where the total energy expenditure can be greater than 10 times that at rest) exogenous and endogenous lactate make up the majority of CHO-energy used by the body at that time ( 104) .
  • lactate including vascularly supplied exogenous lactate, can play an important role as a body energy source in all of them.
  • the [lactate] level at which the beneficial effects of exogenously supplied lactate occur is above normal ( 1 - 2mM), generally about 4 mM ( 102).
  • normal circulating [lactate] Hence, [lactate] is one target which indicates that sufficient lactate is on board to directly fuel an injured brain or other tissues, to indirectly fuel glucose-dependent tissues such as the brain via GNG, as well as to mitigate acidosis and tissue swelling ( 108) .
  • the invention provides for estimating and targeting patient blood lactate concentration ([lactate]) , both as a target itself and as an intermediate step to estimating and targeting patient fractional GNG in body glucose production.
  • Nutritional support methods and formulations are also disclosed that can be used in conjunction with BES/%GNG estimate, as well as without these measurements.
  • the invention provides systems and methods to guide the administration of lactate or other MCC or other GNG precursor formulations to an injured or critically ill patient.
  • the method can be used in either of two ways: ( 1) as a first step during the interim between the adverse patient illness or injury event and assessment of BES via %GNG.
  • the initial lactate/ MCC /GNG precursor infusion rate is about 3-4.5 mg/kg/min, where kg is kg of patient body weight and 3 and 4.5 mg are the amounts of MCC or GNG precursor such as sodium lactate.
  • lactate levels are adequate to (a) directly fuel the brain and other tissues, (b) indirectly fuel tissues with obligatory glucose needs (glucose created via GNG) , (c) mitigate tissue swelling by decreasing intracranial pressure, and (d) mitigate metabolic or respiratory acidosis by affecting hydrogen ion removal through lactate shuttling as well as by and providing a strong anion.
  • Other standard clinical values such as blood pH, electrolyte, total dietary calories and glucose levels, can also be targeted in various aspects of the invention.
  • the invention provides a method for estimating the lactate or other MCC or GNG precursor infusion rate needed to provide patient needs between the time of injury and assessment for BES by determining fractional gluconeogenesis of a patient.
  • the method commences with administering at a lactate or other MCC or GNG precursor infusion rate, as described above, taking a small venous or arterial blood sample from the patient, analyzing [lactate], and adjusting the infusion rate to maintain the target blood [lactate] over time.
  • a small (20- 100 ⁇ ) sample of arterial, venous, finger or earlobe blood is typically used to measure [lactate].
  • the invention provides for the analysis of blood [lactate] by means of a clinical blood gas analyzer or similar device that is used routinely to determine blood acid/base status in a clinical setting.
  • the invention also provides for the analysis of blood [lactate] by means of an approved portable, hand-held or other device as used in laboratory, clinical or field assessments in resting individuals or athletes or others performing vigorous physical exercise. Such devices are readily available, inexpensive, and used by sports medicine practitioners, athletes and coaches as are portable heart rate monitors.
  • handheld portable lactate analyzers are accurate in the mM range and can be used to establish a target a LC value or range while ill or injured persons are transported to clinical facilities.
  • New, more portable and more sophisticated apparatus for analyzing [lactate], as well other biomarkers on interest in the invention are constantly being developed and are contemplated by the invention.
  • the formulations of the invention may also include one or more salts, one or more of Na + , K + , Ca ++ , Mg ++ , and H2PO4", and have an osmolality of less than about 310 mOsm, where the MCCs or GNG precursors are lactate or pyruvate or both.
  • a stock formulation with an osmolality » 3,000 mOsm can be used so long as it is diluted with sterile hypotonic or isosmotic solutions (distilled water, half normal or normal physiological, 154 mM saline, so that the solution entering the body has an osmolarity of less than of about 310 mOsm, and in some cases less than about 1 ,000 mOsm.
  • the formulation may be administered at a rate of about 10-50 micro moles per kg of body weight per minute ⁇ Moles/kg/min), where kg is kg of patient body weight and 10-50 ⁇ is the amount of lactate or other MCC or GNG in the formulation, administered and the infusion rate increased or decreased if the measured blood [lactate] differs from the target value or values.
  • lactate was once thought to be a waste product of metabolism owing to oxygen insufficiency and a cause of muscle fatigue and soreness, largely based on the classic papers of the 1920s and 1930s papers by Hill, Margaria and Meyerhof (107, 1 1 1 , 1 14).
  • lactate shuttle theory lactate is viewed as an energy fuel source, a GNG precursor and a signaling molecule, in other words a lactormone (5, 106). Lactate is produced continuously under fully aerobic conditions and is an essential metabolic intermediate at the crossroads of the pathways of carbon metabolism (5-7). In the outdated concept lactate was a liability. In the contemporary view lactate is a metabolite of great utility and importance.
  • lactate concentration or [lactate] is also called lactatemia.
  • Hyperlactatemia refers to elevated blood [lactate], as generally considered greater than that of rest (about l-2mM).
  • LT lactate threshold
  • OBLA onset of blood lactate accumulation
  • the target blood [lactate] of 4 mM refers to hyperlactatemia induced by exogenous vascular infusion of the current invention.
  • Such a target [lactate] provides sufficient lactate to provide fuel energy, material for gluconeogenesis, and anti-inflammatory and buffering capacity.
  • lactate shuttle to describe the exchange and use of lactate as an energy source within, between and among cell compartments, cells, tissues and organs. Since the original articulation of discovery, intracellular and cell-cell lactate shuttles have been described in the literature (vide supra). As well, others scientists have recognized generality of the principle and have described lactate shuttles within the brain (33, 64, 1 15, 1 18).
  • one aspect of the invention provides for infusion of a formula
  • the target [lactate] concentration of the invention is in some cases, above about 0.5 to ImM, 0.5 to 1 mM being the bottom of the normal range for [lactate]. In other embodiments, it is above about 2 mM, 2mM being the top of the normal range for [lactate]. In other embodiments it is above about 4 mM, 4 mM being the hyperlactemia level where beneficial effects occur all the way to about 8 mM. In another embodiment it is this entire range of normal to quite high, about 0.5-8 mM.
  • [0291]Using such a target [lactate] range can be an interim target until BES assessment via %GNG estimation becomes available. It also works in the invention as a stand-alone since high levels of [lactate] are generally well tolerated by patients. Thus it makes sense to err on the high side of [lactate]. Infusion of MCC or GNG precursor certainly raises blood [lactate], but it generally does not affect blood [glucose] (24, 55, 56).
  • lactate metabolic clearance rate which is lactate Rd/ [lactate] (4, 53, 102, 1 16, 1 17). Nonetheless, by means of commencing with exogenous lactate to achieve a stable blood [lactate], the invention provides sufficient lactate to provide nutritive support directly to an injured brain and other tissues, both directly as lactate, as well as indirectly via GNG.
  • the resulting blood [lactate] might be 2 mM. Presentation of a low (about ⁇ 2 mM) blood [lactate] will be interpreted to represent the presence of a hypermetabolic state with increased demands for lactate as fuel and GNG precursor, and will typically lead to an increase in the infusion rate, according to a preferred embodiment of the invention.
  • the target blood [lactate] range can be as low as 0.5-2 mM, whereas in the absence of %GNG information, a range of about 4 mM and in some embodiments up to about 8 mM is desirable.
  • approximately 3 mg/kg/min may continue until periodic blood sampling indicates that blood [lactate] reaches 4mM, at which time the infusion rate will be maintained or adjusted up or down to maintain blood [lactate] at that target level.
  • the combination of enteral and parenteral nutrition will be maintained or adjusted to achieve the target of 25% GNG at which time exogenous MCC or GNG precursor infusion rate can be adjusted to maintain arterial blood [lactate] in the range of 1-2 mM (vide supra).
  • Intrenteral nutrition can eventually be diminished or curtailed when enteral nutritional delivery is adequate to normalize BES, but intravascular Na + -L-(+) -Lactate infusion may be maintained or restarted if the patient's BES indicates a need to supplement enteral nutrition and achieve approximately 25% GNG.
  • Na + -L-(+)-Lactate may also be used to manage intracerebral pressure ("ICP").
  • the invention in a preferred embodiment, shall commence intravascular infusion of Na + -L-(+) -Lactate at the rate of 3 mg/kg/min.
  • the MCC or alternate embodiment infusion rate of approximately 3 mg/kg/min will continue until periodic blood sampling indicates that blood [lactate] reaches 4 mM, at which time the infusion rate will be maintained or adjusted up or down to maintain blood [lactate] at the target level.
  • %GNG data When %GNG data become available, the combination of enteral and parenteral nutrition will be maintained or adjusted to achieve the target of 20-25% GNG in some embodiments, and 15-35% in others.
  • exogenous MCC or GNG precursor infusion may be adjusted to maintain arterial blood [lactate] in the range of 1 - 2 mM (vide supra).
  • Parenteral nutrition will eventually be stopped when enteral nutritional delivery is adequate, but the intravascular Na + -L-(+)-Lactate infusion can be maintained or restarted if the patient's BES indicates a need to supplement enteral nutrition to achieve approximately the desired %GNG, or if the clinician decides to augment cerebral nutrition or to manage ICP.
  • the invention shall commence intravascular infusion of Na + - L-(+)-Lactate at the rate of 3 mg/kg/min plus parenteral (intravascular) nutritive support according to the AMDRs and TEE estimates as given by the IOM.
  • the MCC or alternate embodiment infusion rate of approximately 3
  • the invention shall commence intravascular infusion of Na + - L-(+)-Lactate, MCC or GNG precursor at the rate of 3 mg/kg/min plus parenteral
  • nutritive support treatment targets are 15-35% GNG or 20-25 %GNG.
  • plasma [lactate] is targeted at 4 mM.
  • plasma [glucose] is targeted as 5-7mM.
  • enteral and parenteral administration rates can be achieved by adjusting enteral and parenteral administration rates either singularly, or in combination.
  • Dextrose and/or insulin therapy may be indicated above a certain [glucose] such as 7.8, or below 5.6 mM. Rates of infusion of Dextrose should not exceed the endogenous glucose Rd (2-3 mg/kg/min) as this will cause a hyperglycemic condition.
  • carbohydrate energy sources (muscle glycogen, blood lactate, liver glycogen and blood glucose) are the predominant energy sources (103).
  • energy flux may increase more than an order of magnitude at a time when the capacity for enteral nutrient delivery is limited not by access to fluids and solid foods, but by gastric emptying and intestinal absorption.
  • the prime example being professional male cyclists, with single component drinks ⁇ e.g., 100% glucose (i.e., dextrose) ⁇ , the rates of gastric emptying and intestinal absorption approximate 1 g/min when the solute concentration is 6 g% (6 g/ 100 ml or 60 g/ 1 ,000 ml) when consumed at the rate of » 1 ,000 ml/hr.
  • transporters for lactate, glucose, fructose, acetate, and amino acids Expressed in the intestinal mucosa are transporters for lactate, glucose, fructose, acetate, and amino acids, among others. Further, some transporters are symporters, also called symports, meaning that they cotransport other substances, in the instance of lactate and glucose transporters, the co-transported moiety is sodium ion (Na + ). The presence of sodium-mediated symports is efficacious in terms of energy, electrolyte and water absorption.
  • These intestinal transporters accomplish what is termed the facilitated transport of solutes.
  • cellular energy sources such as adenosine triphosphate ("ATP") are not used, but viewed in three dimensions transporters are structured in such a way as to form channels, specific for the particular metabolite, that can move down a concentration gradient from intestine to portal blood.
  • transporters While not properly classed as enzymes, transporters display Michaelis-Menten kinetics, meaning that their transport capability possesses unique characteristics such as sensitivity to [substrate], (kM), and maximal rate of substrate transport (Vmax).
  • Another key feature of transporters is that they demonstrate the characteristic termed saturation, where no further increase in transport despite increased solute availability once Vmax is achieved. Hence, because of the abundance of multiple intestinal solute transporters, each functioning
  • solute transport from intestinal lumen to portal blood can be accomplished.
  • aquaporins facilitate the movement of water down concentration gradients.
  • water follows the solutes, in other words, water moves to minimize the osmotic pressure differences exerted by solutes in different exchangeable compartments, such as between the intestinal lumen and portal blood.
  • solutes in other words, water moves to minimize the osmotic pressure differences exerted by solutes in different exchangeable compartments, such as between the intestinal lumen and portal blood.
  • the transport of more carbohydrate energy forms move more Na + ions, and more water follows.
  • sports drinks containing sub-saturating levels of multiple carbohydrate and amino acid energy forms move more energy, fluid and electrolytes than do single or dual solute-containing sports drinks.
  • lactate salts e.g., Na + -lactate, arginyl-lactate, glycerol tri-lactate
  • glycerol tri-acetate e.g., hexoses (glucose and fructose), disaccharides such as sucrose (glucose + fructose), maltodextrins (glucose polymers) and amino acids.
  • lactate salts e.g., Na + -lactate, arginyl-lactate, glycerol tri-lactate
  • glycerol tri-acetate e.glycerol tri-acetate
  • hexoses glucose and fructose
  • disaccharides such as sucrose (glucose + fructose)
  • maltodextrins glucose polymers
  • Sanguisal ⁇ Na + -, K + -, Ca ++ -, Mg ++ -L-(+)-lactate, and NaH 2 P0 4 ⁇ in the ratio of about 145, 4, 2.5, 1.5, and 1.0.
  • Sanguisal would provide electrolytes (Na + , K + , Ca ++ , Mg ++ , and 3 ⁇ 4 ⁇ 0 4 -) as well as energy substrate (lactate).
  • arginyl-lactate, dextrose, fructose, sucrose, maltodextrin and amino acids in addition to arginine e.g., glycine, alanine, glutamate, glutamine, leucine, isoleucine and valine
  • arginine e.g., glycine, alanine, glutamate, glutamine, leucine, isoleucine and valine
  • the formulation could include fructose and maltodextrins (glucose polymers) that are not appropriate for vascular infusion.
  • the drink could consist of: 0. 17% Sanguisal, 1.00% arginyl lactate and/or glycerol tri-lactate, 2.40% dextrose, 2.43% maltodextrin, and 2.00% fructose.
  • GTA glycerol tri-acetate
  • the components of dextrose and maltodextrins could be combined to provide 4.8% of either; the fructose and dextrose components could be combined to provide 4.4% of total as sucrose (cane or beet sugar), and the Sanguisal, arginyl-lactate plus GTL and GTA component could be combined to provide 1.0-2.0 % of either.
  • the inclusion of alanine, branched chain and other amino acids to the level of 1% would result in systematic reductions in the concentrations of other amendments keeping the total solute content at about 8% (w/v).
  • the suggested consumption of the energy drink would be > 1 g/ min at the highest intensity, but at 50% of maximal workload (e.g., brisk walking) the consumption would be 0.5 g/min.
  • Administering/ drinking of oral sports drink can be done with the measurement of blood [lactate] using a concentration meter and a small blood sample to monitor blood [lactate] during training.
  • An individual could use the measurement of blood [lactate] at rest and during exercise to augment the formulations and consumption of the sports drinks depending on training goals and type of activity. For example, by raising blood lactate concentration during exercise by 0.5 to 1.0 mM by the consumption of lactate- or fructose-containing beverages ( 109, 1 10), and thereby conserving endogenous
  • performance may be improved (speed, endurance, duration, among other measure) ( 1).
  • performance may be improved (speed, endurance, duration, among other measure) ( 1).
  • a hyperinsulinemic- euglycemic glucose clamp to assess insulin action in a diabetic
  • Lactate-containing and other GNG precursor or MCC drinks offer the advantage of providing oxidizable fuel most rapidly ( 1 , 104).
  • lactate is a major gluconeogenic precursor (24, 54, 1 13)
  • lactate in a sport drink will indirectly support blood glucose homeostasis during hard exercise by providing substrate for GNG and reducing liver and muscle GLY.
  • lactate anion is a buffer. Providing dextrose in a sports drink will directly support blood glucose homeostasis and help minimize hepatic GLY.
  • lactate and glucose in sports drinks are efficacious also because they ate transported by symporters that also move sodium ion from intestinal lumen into the portal circulation.
  • Providing fructose in a sports drink is efficacious as it is flavorful, and also gives rise to hepatic glucose and lactate production.
  • BCAA branched-chain amino acids
  • Providing the amino acid arginine in a sports drink is efficacious because it can be used as a lactate carrier and a precursor to nitric oxide (NO), a vasodilator.
  • Providing glycerol in the form of GTL and GTA in a sports drink is efficacious because it can be used as a carrier for lactate and acetate, and because glycerol is a gluconeogenic precursor.
  • multiple amendments in sports drinks act to reduce the stress of exercise by providing fuel energy, fluid and electrolytes to increase endurance capacity by extending the time of exercise, particularly at high power outputs (1).
  • nutritional formulations contain the label deuterium as deuterium oxide (heavy water), in addition to the other nutritional ingredients of the formulation.
  • the invention is not limited to deuterium or deuterium oxide labeling.
  • the carbohydrates, lipids or proteins of the formulation could be labeled at one or more of the atoms of the molecule and therefore act as the source of delivery of the label to be given to the individual as a bolus and/or continuously.
  • Sites of labeling of the atoms of the molecules of carbohydrate, lipids or proteins can include carbon ( 13 C), hydrogen/deuterium ( 2 H), and nitrogen ( 15 N), among others.
  • ingredients in the formulation contain the label. These ingredients could be specialized drugs for the specific treatment of the individual, anti-inflammatory drugs added to the formulation, agents for the treatment of infection added to the formulation, probiotics, etc. If one or more atom of these molecules are labeled with a stable isotope they can act as the source of delivery of the label to be given as a bolus and/ or continuously. Sites of labeling of the atoms of the molecules of antiinflammatory drugs, agents for the treatment of infection, probiotics, etc., can include carbon ( 13 C), hydrogen/deuterium ( 2 H), and nitrogen ( 15 N), among others.
  • the labeling of any ingredient included in the formulations can be applied to both enteral and parenteral formulations.
  • the targeted use of infusion of tracer D O, or other tracer ingredient in the formulation can enable the measurement of multiple analytes in multiple patient populations. For example, depending on the enrichment of D O and therefore body water enrichment, multiple products can be measured for metabolic flux. This can be useful for simultaneous input functions into the platform for metabolomics, proteomics and fluxomics (inferring, estimating, measuring or predicting rates of metabolic reactions. Examples are precursor (body water) enrichment and product (glucose and lipids) enrichments among others.
  • non-isotope tracing and labeling techniques could be used with the invention as well, though these would require different ways of labeling or tracing molecules, and different calculations.
  • Some examples include indicator dilution using a dye or cold saline for blood flow measurements and Doppler measurements.
  • the infusion of tracer D O will be targeted to approximately 0.5% for all patient populations, in one embodiment. Because an adult and infant have significantly different body weights, the total amount of tracer infusion will differ significantly, but the percentage of body water enrichment will be similar.
  • Figure 1 1 is a flowchart schematically showing methods of the invention, specifically the GNG methods 1101.
  • Various embodiments of the invention use elements of the method flow as shown, but not necessarily all of them. In addition, some elements may be done more than once, or continuously throughout the method.
  • Figure 1 1 includes elements administering a label 1105; taking a blood sample 1107; analyzing glucose or a glucose derivative from the blood sample 1109; obtaining a value for gluconeogenesis 1111 ; obtaining a value for total glucose production (typically
  • the flowchart also can include obtaining a value for fraction of body water labeled 1115, which can be an accurate proxy for separate measurement of total glucose production 1113. It can also include
  • the ultimate method elements of the invention typically include one or more of estimating fractional gluconeogenesis 1119; administering nutritional formulation in order to support nutritional needs 1121, enabled by the estimating fractional
  • the administration of the formulation includes providing, maintaining, increasing, decreasing or ceasing the formulation, parenterally or enterally or both.
  • the flowchart of Figure 1 1 can be understood as a method of assessing the body energy state (BES) and/ or providing targeted nutrition, and in particular a method for estimating fractional GNG and/ or providing targeted nutrition. [0329]Note that some parts of the method can be carried out more than once in the flowchart. For example, administering formulation 1121 can be done after analysis of body energy state, but it can also be done in the beginning before such analysis, as a precautionary matter when it makes sense to err on the high side in terms of nutrition.
  • various parts of the method can be executed on either side of a client-server relationship. So, for instance, obtaining a value for gluconeogenesis 1111 can also be carried out as receiving a value for gluconeogenesis. This would take place, for instance, in a case where label administration, blood sample analysis and data generation for a gluconeogenesis value or values are carried out at one site or on one apparatus and further calculation or manipulation of this data is done at another, for instance, a server that stores and otherwise uses the data gathered from various hospitals over the
  • data generated or received by the invention may be more than one value, as in a set of values, range or ranges of values.
  • an embodiment of the invention as practiced might start with analyzing glucose or a glucose derivative from the blood sample 1109; then obtaining a value for gluconeogenesis 1111; obtaining a value for total glucose production 1113; and estimating fractional GNG 1119.
  • Other parts of the invention such as administering a label 1105; taking a blood sample 1107; and administering formulation 1121 might be carried out separately, for example, on site at a hospital.
  • Figure 12 is a schematic flowchart illustrating the lactate methods 1201. It includes elements taking a blood sample 1205; measuring the blood lactate concentration of the patient 1207; and administrating formulation 1209, by providing, maintaining, increasing, decreasing or ceasing a formulation; and targeting a desired blood lactate range 1211. These elements may be carried out more than once, or not carried out at all in some embodiments.
  • the method of Figure 12 is also compatible with the method of Figure 1 1.
  • blood lactate measurement and/or [lactate] targeting can be carried out before or after the method of Figure 1 1 , or simultaneously with it, to the degree that targeting of [lactate] and fractional GNG and nutritional support are compatible.
  • the invention includes, in preferred embodiments, functions that calculate nutritional dosimetery prescriptions, with these functions are particularized to different populations, for example, TBI, pre-term infants, diabetics, trained athletes, and many other types of patient populations patients. These functions are typically stored in a database. Not only do these functions provide specific formulations, they are also particularized to the biomarkers of each population, for example, a particular %GNG might have a different meaning with regard to status and nutritional prescription in one population versus another.
  • the invention in a preferred embodiment, also has embedded regulatory codes, among other features, that can be updated through software updates.
  • the invention can create complex dosimetery prescriptions for an entire panel of macronutrients and micronutrients, as well as, in some embodiments, drugs, antiinflammatory agents, and other prescribed agents.
  • the approach of the invention can be a theranostics approach, that is, diagnostics and therapeutics tightly coupled for a complete and effective patient solution, also known as companion diagnostics.
  • the invention is compatible with technologies that may exist in the art wherein blood sample measurements can be taken in vivo without actually extracting blood. Taking a blood sample, as described in the invention, may thus include such techniques.
  • the invention as practiced has parts that may be carried out manually or carried out automatically by some apparatus, system or computer, or some combination of both. Ideally, as much of the methods are automated as possible, via software and/or hardware, on one ore more physical machines. For example, a blood sample may be manually taken from a patient and then prepared for analysis by a lab. While most blood samples today are still taken manually by practitioners, there are electronic apparatus for taking blood samples, and they can be computer or
  • formulation and/ or label can be done by manipulation of drip rate, or such administration can be handled automatically, and rate of administration controlled by hardware or computer.
  • Figure 13 is a schematic system illustration 1301 of a fractional GNG and nutritional support system. Various embodiments may not include all of these elements, and some may be duplicated.
  • the apparatus may include a label administration module 1305; a blood sample module 1307; a glucose analyzer module 1309; a gluconeogenesis calculation module 1311; and a total glucose calculation module 1313.
  • the invention can include a body water fraction module 1315, which can provide a body water fraction value as an accurate proxy for the total glucose calculation of 1313. It can also include an absolute rate of glucose production module 1317.
  • the invention typically will include one or more of a fractional gluconeogenesis estimation module 1319 that provides the fractional GNG estimate of the invention; a nutritional formulation administration module 1321, enabled by the fractional gluconeogenesis estimate that controls formula administration; and a fractional GNG range targeting module 1323 that works with 1321 to achieve the targeting.
  • the system also includes an information bus 1351 by which the apparatus modules can
  • the information bus 1351 should be understood generically as any mode of effective communication, and each module of the invention may communicate by different modes with any of the other modules.
  • the information bus 1351 can include the internal information bus of a particular processor, hardware, or computer by which internal components communicate, it can be a network such as a local area network, wide area network, or other network, including the Internet or other network by which modules that are not in the same location can communicate.
  • the information bus 1351 may be one or more data transport means, including a local microprocessor bus and/or one or more input/output (I/O) buses.
  • the components may be distributed among multiple devices and/or servers, and configured to communicate via the network(s) and/or wireless systems.
  • the information bus 1351 should also be understood to include even human communication and interaction, such as written, oral or reading a display, such as a graphical user interface ("GUI"), in cases where the invention is practiced with some manual aspects.
  • GUI graphical user interface
  • a blood sample can be fed into a machine that provides an estimate of fractional GNG.
  • the data generated by this machine can be automatically communicated to a device that meters nutritional administration via i.v. It also could have a display that provides information by which a practitioner manually adjusts the formula administration.
  • the information bus 1351 is the reading of the display and memorizing its content or instructions by a practitioner to manually execute formulation administration.
  • the apparatus of Figure 13 thus contemplates completely automated modules and communication, but also allows for some manual components.
  • Figure 14 is a schematic system illustration 1401 of a system for blood lactate measuring targeting. It includes elements of a blood sample module 1411; a blood lactate concentration measurement module that provides blood lactate concentration measurement 1413; and a formulation administration module 1415, that operates by providing, maintaining, increasing, decreasing or ceasing a formulation. It also includes a blood lactate range targeting module 1417, which works with 1415 to achieve a target blood lactate range (clamp).
  • the system includes an information bus 1451 by which the apparatus modules can communicate.
  • the information bus 1451 should be understood generically as any mode of effective communication, and each module of the invention may communicate by different modes with any of the other modules.
  • the information bus 1451 can include the internal information bus of a particular processor, hardware, or computer by which internal components communicate, it can be a network such as a local area network, wide area network, or other network, including the Internet or other network by which modules that are not in the same location can communicate.
  • the information bus 1451 may be one or more data transport means, including a local microprocessor bus and/or one or more input/output (I/O) buses.
  • the components may be distributed among multiple devices and/or servers, and configured to communicate via the network(s) and/or wireless systems.
  • the information bus 1451 should also be understood to include even human communication and interaction, such as written, oral or reading a display, such as a graphical user interface ("GUI"), in cases where the invention is practiced with some manual aspects.
  • GUI graphical user interface
  • a blood sample can be fed into a machine that provides an estimate of fractional GNG.
  • the data generated by this machine can be automatically communicated to a device that meters nutritional administration via i.v. It also could have a display that provides information by which a practitioner manually adjusts the formula administration.
  • the information bus 1451 is the reading of the display and memorizing its content or instructions by a practitioner to manually execute formulation administration.
  • the apparatus of Figure 14 thus contemplates completely automated modules and communication, but also allows for some manual components.
  • This system is also compatible with the system of Figure 13 in that one extant system can have elements of both and be capable of carrying out the functions of both Figure 13 and Figure 14.
  • lactate clamp As one embodiment of the system/ apparatus of the invention, consider the targeting of lactate ranges (lactate clamp).
  • the system can include a small lactate concentration meter for real-time measurement and feedback on lactate ranges, for example at the bedside or during training.
  • the invention can provide raw data on
  • [lactate] or have simple instructions using an LCD display or colored lights, e.g., red to instruct the user to reduce ingestion/ infusion and green to instruct the user to increase ingestion/ infusion, or some other user interaction interface such as a GUI.
  • It can be embodied as an apparatus with a lactate meter and a SOC system on chip ("SOC") with some combination of hardware and software that takes the electronic results from the insertion of a biological sample (blood drop) and implements an algorithm to calculate and present a prescription to the user. This prescription could be available to the user bedside or networked for continued analysis, sharing, comparison of historic or changing conditions and database storage.
  • the invention can be embodied as firmware, software, SOC or even a total-solution metering device comparable with readily available [lactate] meters on the market.
  • a mass spectrometer of some sort would be required as part of the system.
  • Table-top mass spectrometers and even handheld and chip-sized devices are now available.
  • a practical implementation of the invention would be a specialized mass spectrometer to measure specific glucose fragmentation patters as described above.
  • Such devices can be networked wirelessly as clients to software as a service (“SAAS”) solutions with website server services to such clients. Stand-alone and internal network solutions can also be implemented.
  • SAAS software as a service
  • the invention contemplates manual implementations of the invention.
  • one or more of fractional body water labeling, [lactate], nutritional formulation administration rates could be read and logged by a practitioner into a system and then stored on-site or on system servers, or in the Internet cloud.
  • An attending clinician could then access and monitor the patient over time and treatment and increase, decrease, maintain or cease the prescription based on the measurement of [lactate] or %GNG, or simply follow instructions as calculated and displayed by the system.
  • the device could have software that could be useful for a meter manufacturer or SOC designer so a measurable event can be programmed to produce a prescription that will be an actionable event instructing the nurse, clinician, athlete, worker, etc., to change oral ingestion or infusion rate, or both.
  • formula administration can be carried out automatically by the system, e.g.,
  • the invention provides for raising blood [lactate] between 0.5 and 1 mM above a concentration measurement comparable to ingestion based on water alone. So, during exercise an athlete could have lactate concentration measured with no ingestion or ingestion consisting of only water to determine the background
  • a variable amount of a formulation of sports drink could be administered to raise the blood [lactate] above background. This would allow the athlete to consume the optimal amount of fuel for the working muscle during for his or her current state of body energy flux.
  • the invention could display the proper actionable steps (drink amount and rate) or
  • fractional GNG expressed as ion intensities ([ion 170/ 169]/6) / ([ion 332/33 l]-[ion 170/ 169]) ⁇ 15%
  • decrease infusion rate of exogenous energy formulation if > 15% and ⁇ 30%
  • maintain infusion rate of exogenous energy formulation if > 30%, then increase infusion rate of exogenous energy formulation.
  • %GNG energy balance for the platform
  • biomarkers and metrics such as nitrogen balance, albumin, pre-albumin, hemoglobin, sodium (measured as concentration, delivery in kg/day, mEq/kg and total volume of fluids, among others), potassium, calcium, magnesium, phosphorus, urine urea nitrogen balance, total nitrogen balance,
  • osmotic pressure blood and urine osmolality
  • total calories of percentage of carbohydrate, fat and protein (and fractions of each) and delivery rate of enteral and/or parenteral nutrition.
  • nitrogen balance is a measure of the adequacy of protein intake and can estimate the patient's current protein requirements. The calculation of nitrogen balance is based on the total daily intake of nitrogen minus the daily excretion.
  • Nitrogen Balance Nitrogen Intake - Nitrogen losses
  • Nitrogen Intake Protein Intake (g/day) / 6.25
  • Nitrogen Losses Urinary Urea Nitrogen (g/day) + 4g
  • Urinary Urea Nitrogen is typically determined from a 24-hour urine collection and 4g is a correction factor to account for miscellaneous nitrogen losses.
  • the method to determine BES is as described above as a non-diabetic patient except the baseline is shifted up.
  • diabetic will go from a nourished BES to a catabolic state of BES similar to a non-diabetic patient, but the values will be elevated as compared to the non-diabetic patient.
  • the invention can accommodate for various patient populations and individual phenotypes, such as type 2 diabetes.
  • type 2 diabetes the same measurable event happens for both normal and diabetes, but the baseline %GNG is shifted upward for the diabetes patient.
  • the normal control subject reached a fractional GNG of 70% whereas the type 2 diabetic subject reached 88% fractional GNG. It would be best to add a numerical example here.
  • Figure 15 is a block diagram of an exemplary computing system that may be utilized to practice aspects of the present disclosure.
  • Figure 15 illustrates an exemplary computing device 1500 that may be used to implement an embodiment of the present systems and methods.
  • the system 1500 of Figure 15 may be implemented in the contexts of the likes of computing devices, networks, servers, or combinations thereof.
  • the computing device 1500 of Figure 15 includes one or more processors 1510 and main memory 1520.
  • Main memory 1520 stores, in part, instructions and data for execution by processor 1510.
  • Main memory 1520 may store the executable code when in operation.
  • the system 1500 of Figure 15 further includes a mass storage device 1530, portable storage device 1540, output devices 1550, user input devices 1560, a display system 15150, and peripheral devices 1580.
  • main memory 1520 is used by storage for storing data.
  • FIG. 15 The components shown in Figure 15 are depicted as being connected via a single bus 1590. The components may be connected through one or more data transport means.
  • Processor unit 1510 and main memory 1520 may be connected via a local microprocessor bus, and the mass storage device 1530, peripheral device(s) 1580, portable storage device 1540, and output devices 1550 may be connected via one or more input/ output (I/O) buses.
  • I/O input/ output
  • Mass storage device 1530 which may be implemented with a magnetic disk drive or an optical disk drive, is a non-volatile storage device for storing data and instructions for use by processor unit 1510. Mass storage device 1530 may store the system software for implementing embodiments of the present technology for purposes of loading that software into main memory 1520. In some embodiments, portable storage device 1540 is used by storage for storing data.
  • Portable storage device 1540 operates in conjunction with a portable non-volatile storage medium, such as a floppy disk, compact disk, digital video disc, or USB storage device, to input and output data and code to and from the computer system 1500 of Figure 15.
  • a portable non-volatile storage medium such as a floppy disk, compact disk, digital video disc, or USB storage device
  • the system software for implementing embodiments of the present technology may be stored on such a portable medium and input to the computer system 1500 via the portable storage device 1540.
  • portable storage device 1540 is used by storage for storing data.
  • User input devices 1560 provide a portion of a user interface.
  • User input devices 1560 may include an alphanumeric keypad, such as a keyboard, for inputting alphanumeric and other information, or a pointing device, such as a mouse, a trackball, stylus, or cursor direction keys.
  • Additional user input devices 1560 may be comprised of, but are not limited to, devices such as speech recognition systems, facial recognition systems, motion-based input systems, gesture-based systems, and so forth.
  • user input devices 1560 may include a touchscreen.
  • the system 1500 as shown in Figure 15 includes output devices 1550. Suitable output devices include speakers, printers, network interfaces, and monitors.
  • Output devices 1550 may include a liquid crystal display (LCD) or other suitable display device.
  • Display system 1550 receives textual and graphical information, and processes the information for output to the display device.
  • Peripheral device(s) 1580 may include any type of computer support device to add additional functionality to the computer system.
  • Peripheral device(s) 1580 may include a modem or a router.
  • the components provided in the computer system 1500 of Figure 15 are those typically found in computer systems that may be suitable for use with embodiments of the present technology and are intended to represent a broad category of such computer components that are well known in the art.
  • the computer system 1500 of Figure 15 may be a personal computer, hand held computing device, telephone, mobile computing device, workstation, server, minicomputer, mainframe computer, or any other computing device.
  • the computer may also include different bus configurations, networked platforms, multi-processor platforms, etc.
  • Various operating systems may be used including Unix, Linux, Windows, Mac OS, Palm OS, Android, iOS (known as iPhone OS before June 2010), QNX, and other suitable operating systems.
  • Computer-readable storage media refer to any medium or media that participate in providing instructions to a central processing unit (CPU), a processor, a microcontroller, or the like. Such media may take forms including, but not limited to, non-volatile and volatile media such as optical or magnetic disks and dynamic memory, respectively. Common forms of computer-readable storage media include a floppy disk, a flexible disk, a hard disk, magnetic tape, any other magnetic storage medium, a CD-ROM disk, digital video disk (DVD), any other optical storage medium, RAM, PROM, EPROM, a
  • FLASHEPROM any other memory chip or cartridge.
  • Computer program code for carrying out operations for aspects of the present technology may be written in any combination of one or more programming languages, including an object oriented programming language such as Python, Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as the "C" programming language or similar programming languages.
  • the program code may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server.
  • the remote computer may be coupled with the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).
  • LAN local area network
  • WAN wide area network
  • Internet Service Provider for example, AT&T, MCI, Sprint, EarthLink, MSN, GTE, etc.
  • Part of the invention may be implemented by a general-purpose computer, embedded circuitry, or some combination of these.
  • the software execution may be accomplished through the use of a program storage device readable by the computer and encoding a program of instructions executable by the computer for performing the operations described above.
  • the program storage device may take the form of any memory known in the art or subsequently developed.
  • the program of instructions may be object code, i.e., in binary form that is executable more-or-less directly by the computer; in source code that requires compilation or interpretation before execution; or in some intermediate form such as partially compiled code and/ or a collection of executable library files.
  • object code i.e., in binary form that is executable more-or-less directly by the computer; in source code that requires compilation or interpretation before execution; or in some intermediate form such as partially compiled code and/ or a collection of executable library files.
  • the precise forms of the program storage device and of the encoding of instructions are immaterial here.
  • the invention also contemplates use of computer networks known in the art, including but not limited to, intranets such as corporate networks, local and wide area networks, the Internet and the World Wide Web. Wire and wireless communication and
  • Muscle accounts for glucose disposal but not blood lactate appearance during exercise after acclimatization to 4,300 m. Journal of applied physiology 72: 2435-2445, 1992.
  • Gluconeogenesis is not regulated by either glucose or insulin in extremely low birth weight infants receiving total parenteral nutrition. J Pediatr 158: 891-896, 201 1.
  • Colberg SR Casazza GA, Horning MA, and Brooks GA. Increased dependence on blood glucose in smokers during rest and sustained exercise. Journal of Applied Physiology 76: 26-32, 1994.
  • Emhoff CA Messonnier LA, Horning MA, Fattor JA, Carlson TJ, and Brooks
  • Kalhan SC Parimi P
  • Van Beek R Van Beek R
  • Gilfillan C Saker F
  • Gruca L Sauer PJ.
  • Landau BR Quantifying the contribution of gluconeogenesis to glucose production in fasted human subjects using stable isotopes. Proc Nutr Soc 58: 963-972, 1999. Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, and Kalhan SC. Use of 2H20 for estimating rates of gluconeogenesis. Application to the fasted state. J Clin Invest 95: 172- 178, 1995.
  • GA Measurement of gluconeogenesis in exercising men by mass isotopomer distribution analysis. Journal of applied physiology 93: 233-241 , 2002.
  • Emhoff CA Messonnier LA, Horning MA, Fattor JA, Carlson TJ, and Brooks

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Nutrition Science (AREA)
  • Inorganic Chemistry (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Food Science & Technology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Polymers & Plastics (AREA)
  • Mycology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Obesity (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des systèmes, des techniques et des procédés qui permettent d'estimer l'état métabolique ou le flux métabolique, par exemple l'état énergétique du corps (BES) d'un patient. Le BES donne un aperçu profond des besoins nutritionnels du patient, permettant ainsi une sorte de régulation délicate de la glycémie concernant le patient. L'invention concerne des systèmes et des procédés qui permettent d'estimer la gluconéogenèse fractionnelle. L'invention concerne également des systèmes et des procédés qui permettent d'estimer et de cibler la concentration en lactate sanguin d'un patient, à la fois en tant que cible elle-même et en tant qu'étape intermédiaire pour estimer et cibler la production de glucose de gluconéogenèse fractionnelle. L'invention concerne également des procédés de support nutritionnel et des formulations. L'invention est appropriée pour toute sorte de patients, y compris ceux qui sont blessés, tels que par une lésion cérébrale traumatique, une maladie ou d'autres états qui provoquent un stress sur le système métabolique.
EP13848522.2A 2012-10-25 2013-10-24 Procédés et systèmes pour estimer les besoins nutritionnels de patients humains et d'autres patients et pour prendre en charge de tels besoins nutritionnels Ceased EP2912161A4 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP19151852.1A EP3505167A1 (fr) 2012-10-25 2013-10-24 Prendre en charge les besoins nutritionnels de l'homme et d'autres patients

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US201261795819P 2012-10-25 2012-10-25
US13/903,929 US9808031B2 (en) 2012-10-25 2013-05-28 Systems and methods to estimate nutritional needs of human and other patients
US13/903,939 US9500657B2 (en) 2012-10-25 2013-05-28 Formulations containing labels for medical diagnostics
US13/903,936 US9557334B2 (en) 2012-10-25 2013-05-28 Formulations and methods to provide nutrition to human and other patients
US13/957,977 US20140120238A1 (en) 2012-10-25 2013-08-02 Formulations and methods to provide nutrition to human and other patients
US13/957,872 US20140121270A1 (en) 2012-10-25 2013-08-02 Formulations and methods to provide nutrition to human and other patients
US13/957,813 US8927490B2 (en) 2012-10-25 2013-08-02 Systems and methods to estimate nutritional needs of human and other patients
US14/043,703 US9232815B2 (en) 2012-10-25 2013-10-01 Blood lactate range targets and nutritional formulations and protocols to support patients
US14/061,640 US9897609B2 (en) 2012-10-25 2013-10-23 Systems and apparatus to estimate nutritional needs of human and other patients and to support such nutritional needs
PCT/US2013/066597 WO2014066628A2 (fr) 2012-10-25 2013-10-24 Procédés et systèmes pour estimer les besoins nutritionnels de patients humains et d'autres patients et pour prendre en charge de tels besoins nutritionnels

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP19151852.1A Division EP3505167A1 (fr) 2012-10-25 2013-10-24 Prendre en charge les besoins nutritionnels de l'homme et d'autres patients

Publications (2)

Publication Number Publication Date
EP2912161A2 true EP2912161A2 (fr) 2015-09-02
EP2912161A4 EP2912161A4 (fr) 2016-08-24

Family

ID=53056453

Family Applications (2)

Application Number Title Priority Date Filing Date
EP13848522.2A Ceased EP2912161A4 (fr) 2012-10-25 2013-10-24 Procédés et systèmes pour estimer les besoins nutritionnels de patients humains et d'autres patients et pour prendre en charge de tels besoins nutritionnels
EP19151852.1A Withdrawn EP3505167A1 (fr) 2012-10-25 2013-10-24 Prendre en charge les besoins nutritionnels de l'homme et d'autres patients

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP19151852.1A Withdrawn EP3505167A1 (fr) 2012-10-25 2013-10-24 Prendre en charge les besoins nutritionnels de l'homme et d'autres patients

Country Status (6)

Country Link
EP (2) EP2912161A4 (fr)
JP (2) JP2016502654A (fr)
KR (1) KR102172971B1 (fr)
AU (2) AU2013334526B2 (fr)
CA (1) CA2889348A1 (fr)
WO (1) WO2014066628A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6730196B2 (ja) * 2014-05-21 2020-07-29 ソシエテ・デ・プロデュイ・ネスレ・エス・アー 個人向けの栄養素含有量を有する栄養組成物を製造するためのシステム、方法、及び装置
AU2016208457B2 (en) 2015-01-23 2022-03-24 Société des Produits Nestlé S.A. Method for determining the distinctive nutritional requirements of a patient

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5420107A (en) 1990-01-26 1995-05-30 Brooks; George A. Method and composition for energy source supplementation during exercise and recovery
US5910403A (en) * 1997-05-15 1999-06-08 The Regents Of University Of California Methods for measuring cellular proliferation and destruction rates in vitro and in vivo
US6329208B1 (en) * 1997-07-16 2001-12-11 Board Of Regents, The University Of Texas System Methods for determining gluconeogenesis, anapleurosis and pyruvate recycling
US6482853B1 (en) 2000-07-12 2002-11-19 George A. Brooks Lactate thiolester for cardiac energy resuscitation and prevention of reperfusion injury and use as an energy supplement during exercise and recovery
US7256047B2 (en) * 2001-05-01 2007-08-14 Board Of Regents, The University Of Texas System Measurement of gluconeogenesis and intermediary metabolism using stable isotopes
AU2002365911A1 (en) * 2001-08-06 2003-09-04 Vanderbilt University System and methods for discriminating an agent
MY135783A (en) * 2001-09-07 2008-06-30 Meiji Dairies Corp Nutritional composition for controlling blood sugar level
CA2494715C (fr) * 2002-07-30 2014-07-08 The Regents Of The University Of California Procede de mesure automatique a grande echelle des taux de flux moleculaire par spectrometrie de masse
US20050027005A1 (en) * 2003-08-02 2005-02-03 Matthias Boldt Nutrient compositions and methods for sustenance and promotion of positive metabolic energy levels in a targeted manner
WO2006119355A2 (fr) * 2005-05-03 2006-11-09 Albert Einstein College Of Medicine Of Yeshiva University Modulation hypothalamique du metabolisme du glucose chez les mammiferes par l'intermediaire de nutriments
EP1731145A1 (fr) * 2005-05-25 2006-12-13 Institut National De La Recherche Agronomique Utilisation de glycérol pour ameliorer la fonction cardiaque
US20090285909A1 (en) * 2006-04-03 2009-11-19 Leverve Xavier M Lactate and Calcium Containing Pharmaceutical Composition and Uses Thereof
US7503937B2 (en) * 2006-07-03 2009-03-17 Ossur Hf Prosthetic foot
CN101939011B (zh) * 2008-02-07 2012-10-10 雀巢产品技术援助有限公司 用于影响由剧烈的体力活动中恢复的组合物和方法

Also Published As

Publication number Publication date
EP2912161A4 (fr) 2016-08-24
JP2016502654A (ja) 2016-01-28
AU2018229477A1 (en) 2018-10-04
JP2020101549A (ja) 2020-07-02
AU2013334526A1 (en) 2015-06-11
KR102172971B1 (ko) 2020-11-03
EP3505167A1 (fr) 2019-07-03
KR20150076229A (ko) 2015-07-06
WO2014066628A2 (fr) 2014-05-01
AU2013334526B2 (en) 2018-06-14
CA2889348A1 (fr) 2014-05-01
WO2014066628A3 (fr) 2014-08-28

Similar Documents

Publication Publication Date Title
US20210127728A1 (en) Systems and methods for monitoring of fractional gluconeogenesis and targeting of fractional gluconeogenesis via nutritional support
US9897609B2 (en) Systems and apparatus to estimate nutritional needs of human and other patients and to support such nutritional needs
AU2018229477A1 (en) Methods and systems to estimate nutritional needs of human and other patients and to support such nutritional needs
US20200158714A1 (en) Continuous monitoring of blood lactate and ongoing targeting of blood lactate via nutritional support
US9232815B2 (en) Blood lactate range targets and nutritional formulations and protocols to support patients
US10905148B2 (en) Systems and methods for monitoring of blood lactate and targeting of blood lactate via nutritional support

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20150522

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20160727

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/047 20060101AFI20160721BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20170329

REG Reference to a national code

Ref country code: DE

Ref legal event code: R003

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 20190115