Cysteine Supplementation in Critically Ill Neonates

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Brief Title

Cysteine Supplementation in Critically Ill Neonates

Official Title

Effect of Cysteine Supplementation on Glutathione Production in Critically Ill Neonates

Brief Summary

      Critically ill babies less than 1 month of age have deficient amounts of the antioxidant
      glutathione and a high incidence of disease associated with oxidative injury compared to
      healthy babies. These diseases include but are not limited to damage to the eyes, lungs, and
      intestines. Frequently becoming chronic and potentially life threatening, these diseases
      result in a significantly decreased quality of life to the infant along with increased costs
      to the infant's family and society.

      The amino acid cysteine comprises a third of the tripeptide glutathione and directly
      influences glutathione production. Older children ill with infection and stable, premature
      neonates administered cysteine supplementation to their diet have been previously shown to
      increase their glutathione production and concentrations. Furthermore, cysteine
      supplementation in the ill children resulted in a quicker resolution of their illness.

      Although most critically ill babies require IV nutrition (i.e., TPN) before and during their
      illness, commercially available TPN does not include cysteine as a significant nutrient.
      Cysteine has effectively become a safe and standard supplement to routine TPN in a few major
      hospitals in the U.S.

      The purpose of this study is to evaluate the ability of cysteine supplementation to increase
      glutathione production and concentrations in critically ill babies. Furthermore, the
      investigators want to evaluate whether cysteine supplementation results in less oxidative
      tissue injury and ultimately less severe illnesses. The study will enroll babies admitted to
      the UCLA Medical Center Neonatal Intensive Care Unit (NICU) and they will be chosen at random
      and in a blinded fashion to receive either cysteine or non-cysteine supplementation to their
      routine TPN. Small blood samples along with a single 6 hour infusion of a non-radioactive,
      stable isotope labeled amino acid will be used to measure the production of glutathione as
      well as other compounds in the blood to give a quantitative assessment to the severity of
      illness. Clinical information relevant to the babies' illness and subsequent recovery will be
      recorded.

      The results will be compared between cysteine vs. non-cysteine groups and before vs. after
      individual supplementation. By demonstrating the effect of cysteine supplementation on
      glutathione production, the incidence and/or severity of disease from oxidative injury in
      critically ill babies may be decreased if glutathione production is improved.
    

Detailed Description

      Specific Aims:

      Critically ill neonates have demonstrated low concentrations of the antioxidant glutathione
      and a high incidence of disease associated with oxidative injury compared to healthy
      neonates. Cysteine is considered to be a conditionally essential amino acid for neonates and
      is the rate limiting substrate for the synthesis of glutathione. We hypothesize that
      parenterally-fed, critically ill neonates administered cysteine supplementation will have
      higher concentrations of total glutathione, lower ratios of oxidized to reduced glutathione,
      higher glutathione synthetic rates, lower levels of inflammatory cytokine production and
      lipid peroxidation, and decreased severity of disease associated with oxidative injury
      compared to similarly ill parenterally fed neonates without cysteine supplementation. To test
      this hypothesis, critically ill, parenterally fed neonates assigned randomly to receive a
      cysteine or an isonitrogenous cysteine-free supplement to their TPN (total parenteral
      nutrition) regimen will be prospectively studied in a double-blind fashion according to the
      following specific aims:

        1. to measure total concentrations of erythrocyte glutathione, oxidized to reduced
           (GSSG:GSH) erythrocyte glutathione ratios, and the in vivo fractional and absolute
           synthetic rates of erythrocyte glutathione utilizing a [13C]-glycine tracer,

        2. to measure plasma interleukin-6 (IL-6), tumor necrosis factor (TNF-a), and
           malondialdehyde concentrations as determinants of illness severity and degree of
           oxidative injury reflected by lipid peroxidation,

        3. and, to measure duration of mechanical ventilation, duration of supplemental oxygen, and
           duration of hospitalization as the primary clinical outcomes of disease severity.

      By demonstrating whether cysteine supplementation increases the synthesis and concentration
      of glutathione along with the subsequent decrease in oxidative injury and associated disease,
      the widespread morbidity and mortality for vulnerable, critically ill neonates may be
      improved.

      Background:

      Critically ill neonates treated in the Neonatal Intensive Care Unit (NICU), whether premature
      or full term, experience a high incidence of diseases that may be secondary to or exacerbated
      by oxidative injury. These include a variety of multi-factorial disease processes such as
      respiratory distress syndrome (RDS), persistent pulmonary hypertension (PPHN), chronic lung
      disease (CLD), sepsis, meconium aspiration, retinopathy of prematurity (ROP), and necrotizing
      enterocolitis (NEC). Within NICUs across the U.S. per year, Neonatologists and Pediatric
      Surgeons care for an estimated 100,000 critically ill neonates, of which approximately 35%
      are full-term and up to 20% will ultimately expire of their illnesses despite major advances
      in neonatal care. Some neonatal diseases are well known to have a varying prevalence
      according to neonatal maturity. Premature neonates more commonly suffer from RDS, CLD, ROP
      and NEC, with the most susceptible being the extremely premature. However, 10-15% of neonates
      who develop NEC are full-term and have a resultant mortality rate of up to 35%. Furthermore,
      other disease processes causing significant respiratory distress (e.g., PPHN, pneumonia, and
      meconium aspiration) more commonly occur in full-term neonates.

      The high morbidity of these diseases has a significant impact for the neonate, their parents,
      and society in general. Neonatal survivors of critical illness who are without obvious
      neurologic injury have been found later to have lower IQ's, increased behavioral problems,
      decreased ability to perform normal activities of daily living, decreased scholastic
      abilities, and decreased health-related quality of life compared to healthy children. The
      economic burden to the parents and society from the care of these neonatal illnesses can be
      astounding. For example, the economic costs of neonatal healthcare alone can increase 32-71%
      when a critically ill neonate has NEC compared to appropriately matched controls without NEC.
      Adjusted for inflation to the year 2005, an additional expense of approximately $281,666 is
      expected for every NEC survivor prior to discharge from the NICU (equivalent to $8.45 million
      per year for a single large healthcare center). Similarly, the continued healthcare costs of
      critically ill neonates even after discharge can be insurmountable. Children who were
      survivors of a critical illness as a premature neonate have been shown to require increased
      utilization of Pediatric Intensive Care Unit (PICU) resources (e.g., mechanical ventilation),
      increased length of ICU care, and more frequent readmission to the PICU compared to other
      PICU patients.

      Although cysteine is a non-essential amino acid made from methionine via cystathionine in
      children and adults, most premature and term neonates have a decreased capacity to synthesize
      cysteine due to their low expression of the rate limiting enzyme cystathionase. As a result,
      plasma cysteine and cystine concentrations in critically ill neonates are low compared to
      healthy infants. Unfortunately, plasma cysteine concentrations of neonates receiving
      cysteine-free TPN remain low despite generous methionine intakes and relatively high plasma
      methionine concentrations in TPN fed neonates. This is particularly relevant since cysteine
      is the limiting substrate for the synthesis of the principal intracellular antioxidant in the
      body - glutathione.

      Intracellular glutathione serves many roles in the cell including protection against
      oxidative damage caused by free radicals through glutathione peroxidase and detoxification of
      electrophilic metabolites through multiple glutathione transferases. Thereby, the level of
      glutathione in a specific organ or tissue is thought to be a major determinant of the
      vulnerability of that organ or tissue to oxidative stress. Although the majority of whole
      body glutathione is produced in hepatocytes, most cells, including the erythrocyte, have the
      equivalent capacity to synthesize glutathione de novo from the 3 amino acids cysteine,
      glutamate, and glycine utilizing (-glutamylcysteine and glutathione synthetases. The active
      form of glutathione (reduced or GSH) is also regenerated from recycling of oxidized
      glutathione (glutathione disulfide or GSSG) through glutathione reductase. However, when the
      use of reduced glutathione exceeds the capacity of regeneration, the GSSG is expelled from
      the cell and intracellular glutathione stores are depleted.

      Regardless of the degree of stress or neonatal weight, critically ill neonates have activity
      levels of these glutathione synthetic enzymes comparable to those of adults. Furthermore,
      these neonates demonstrate unimpeded ability to transport amino acids, including cysteine
      derivatives, across cellular membranes. Hence, neonates demonstrate the capacity to
      synthesize glutathione given the appropriate substrates are available. Despite the potential
      ability to synthesize glutathione, low glutathione concentrations and high ratios of GSSG:GSH
      have been demonstrated from the blood, lung, and intestine of critically ill neonates in
      multiple studies. Consequently, a likely limiting factor in the production of glutathione for
      critically ill neonates is the availability of cysteine in their diet.

      Most critically ill neonates receive their nutrition solely through the parenteral route
      during the acute duration of their illness, from a few days to weeks of post-natal life.
      Unfortunately, there is no parenteral amino acid formulation commercially available in the
      U.S. which includes cysteine as a significant nutrient. This is because cysteine is
      relatively unstable and cystine (i.e., cysteine dimer) is insoluble in aqueous solution.
      However, cysteine supplementation to TPN is possible in the form of cysteine-HCl if given
      within 24 hours prior to infusion. Subsequent provision of cysteine in this manner results in
      higher plasma cysteine concentrations in critically ill neonates. Although cysteine-HCl
      supplementation to TPN has been shown to be possible and safe, it is not routine practice in
      current neonatal care. Nevertheless, cysteine-HCl supplementation is standard practice in
      some major neonatal centers in the U.S. in order to augment the calcium and phosphorus
      solubility in TPN, which further benefits growing infants.

      Several in vitro and animal studies demonstrate cysteine supplementation increases
      glutathione concentrations in the blood, liver, and intestines. Cysteine supplementation to
      premature neonatal erythrocytes in cell cultures have demonstrated increased glutathione
      concentrations compared to non-cysteine supplemented controls. Malloy et. al. have shown
      cysteine-HCl supplemented TPN-fed beagle pups have higher concentrations of plasma cysteine
      and hepatic glutathione than unsupplemented TPN-fed pups. Similarly, Pollack et. al. have
      demonstrated intestinal glutathione concentrations significantly increase in premature
      newborn rabbits administered cysteine-HCl supplementation compared to non-supplemented
      controls. Moreover, the colonic glutathione concentrations were found to be similar to those
      of maternally reared, term newborn rabbits.

      As a clinical corollary, human studies in stressed adults with acute respiratory distress
      syndrome have demonstrated elevated concentrations of glutathione and improvements in
      recovery after cysteine supplementation. Septic and malnourished children supplemented with
      enteral cysteine have demonstrated increased glutathione concentrations and in vivo
      glutathione synthetic rates measured utilizing a novel non-radioactive, stable isotope
      methodology. Furthermore, the septic children supplemented with cysteine resolved their
      illnesses quicker than their unsupplemented counterparts. These studies suggest that
      cysteine-HCl supplementation may improve glutathione production and decrease oxidative stress
      in critically ill neonates.

      There has yet to be an investigation confirming that improved glutathione concentrations and
      in vivo glutathione synthetic rates occur in critically ill neonates supplemented with
      cysteine-HCl and that these perturbations lead to a decrease in the amount of oxidative
      tissue injury that these patients endure. This gap in studies serves as a perfect setting for
      our proposed randomized, blinded, placebo-controlled trial that is adequately powered to
      detect a pre-determined difference between the two groups.
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Total RBC glutathione

Secondary Outcome

 Tumor necrosis factor (TNF)

Condition

Sepsis

Intervention

Parenteral cysteine-HCl supplementation

Study Arms / Comparison Groups

 Cysteine
Description:  Subjects that receive cysteine

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Dietary Supplement

Estimated Enrollment

108

Start Date

September 2006

Completion Date

July 2011

Primary Completion Date

March 2011

Eligibility Criteria

        Inclusion Criteria:

          -  mechanically ventilated neonates of all gestational ages and birth weights

          -  less than 1 month of postnatal age admitted to the NICU

          -  SNAP (Score of Neonatal Acute Physiology) > 10

          -  projected requirement for continued parenteral nutrition of at least 1 week duration

        Exclusion Criteria:

          -  renal or hepatic failure

          -  requiring insulin administration

          -  requiring extracorporeal life support

          -  known inherited metabolic disorders

          -  known uniformly fatal congenital anomalies
      

Gender

All

Ages

N/A - 30 Days

Accepts Healthy Volunteers

No

Contacts

Stephen B Shew, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00254176

Organization ID

04-12-035-05

Secondary IDs

5K08HD052885-04


Study Sponsor

University of California, Los Angeles


Study Sponsor

Stephen B Shew, M.D., Principal Investigator, University of California, Los Angeles


Verification Date

February 2010