<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01735552</url>
  </required_header>
  <id_info>
    <org_study_id>51050</org_study_id>
    <nct_id>NCT01735552</nct_id>
  </id_info>
  <brief_title>Transfusion-related Inflammatory Cytokine and Neutrophil Extracellular Trap Quantification in Neonates</brief_title>
  <official_title>Transfusion-related Inflammatory Cytokine and Neutrophil Extracellular Trap Quantification in Neonates.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Utah</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Utah</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Despite many advances in neonatal care, necrotizing enterocolitis (NEC) remains a leading&#xD;
      cause of morbidity and mortality among premature infants. NEC is the most common&#xD;
      life-threatening gastrointestinal emergency encountered in the neonatal intensive care unit,&#xD;
      affecting between 3.8% and 13% of very low birthweight (VLBW) infants (1-3). More recently&#xD;
      interest has intensified regarding the possible association between &quot;elective&quot; red blood cell&#xD;
      (RBC) transfusions in premature infants and the subsequent development of NEC (4-9). On a&#xD;
      physiological basis, a few explanations for transfusion-associated NEC have been proposed: 1)&#xD;
      the physiological impact of anemia that can initiate a cascade of events leading to&#xD;
      ischemic-hypoxemic mucosal gut injury predisposing to NEC [10]; and 2) increased splanchnic&#xD;
      blood flow following RBC transfusion leading to reperfusion injury of gut mucosa.&#xD;
&#xD;
      Aim 1. This study will quantify inflammatory cytokine profiles in anemic infants cared for in&#xD;
      the NICU prior to and after transfusion with packed red blood cells (PRBC), as dictated by&#xD;
      current clinical guidelines for treatment of anemia, and prospectively assess for clinical&#xD;
      signs and symptoms of NEC following each transfusion event.&#xD;
&#xD;
      Aim 2. Polymorphonuclear leukocytes (PMNs) isolated from the pre- and post-transfusion blood&#xD;
      samples will be assessed in vitro for neutrophil extracellular traps (NET) formation.&#xD;
&#xD;
      Aim 3. A) To determine whether significant anemia preceding a RBC transfusion is associated&#xD;
      with impaired intestinal oxygenation, and whether a RBC transfusion temporarily increases&#xD;
      splanchnic oxygenation. We postulate that the CSOR will be low (&lt;0.75) at baseline&#xD;
      measurement in infants with hemodynamically significant anemia, and that RBC transfusion will&#xD;
      temporarily increase intestinal perfusion in that particular group of babies.&#xD;
&#xD;
      B) To determine whether alterations in mesenteric regional oxygenation saturation(rSO2) can&#xD;
      predict the development of NEC in VLBW infants. We hypothesize that overall&#xD;
      cerebro-splanchnic oxygenation ratio (CSOR) values will be significantly lower among very low&#xD;
      birth weight (VLBW) infants that develop NEC, when compared to CSOR values obtained in&#xD;
      infants that do not develop NEC following RBC transfusion.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Unable to recruit participants&#xD;
  </why_stopped>
  <start_date>June 2012</start_date>
  <completion_date type="Actual">April 2015</completion_date>
  <primary_completion_date type="Actual">April 2015</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Serum cytokine content</measure>
    <time_frame>6 hrs</time_frame>
    <description>Plasma samples will be analyzed for the protein content of 13 different cytokines via a multiplexed sandwich capture assay performed at the ARUP Institute for Experimental and Clinical Pathology. The cytokines and chemokines assayed will include: CD40 ligand, interferon-gamma, interleukin-10, interleukin-12, interleukin-13, interleukin-1-β, interleukin-2, interleukin-2-receptor, interleukin-4, interleukin-5, interleukin-6, IL-8, and Tumor Necrosis Factor-alpha. In addition, we will assay components of the complement pathway including: total hemolytic complement, C3a, C5a, and FAB fragments in the alternative complement pathway. Cytokine protein levels before and after transfusion will be compared to each other and to the PRBC sample cytokine content.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assessment of NET formation</measure>
    <time_frame>6 hrs</time_frame>
    <description>PMNs will be isolated from the participant blood samples following removal of the plasma via positive immunoselection. They will then be stimulated in vitro with NET-inducing stimuli such as lipopolysaccharide or platelet-activating factor for 1 hour under standard conditions and assayed for NET formation both qualitatively via confocal microscopy and quantitatively via histone H3 supernatant content as determined by ELISA and/or western blotting.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Tissue oxygenation indexes (TOI) of cerebral (TOI brain ) and splanchnic (TOIabdo) regions</measure>
    <time_frame>53 hrs</time_frame>
    <description>Tissue oxygenation indexes (TOI) of cerebral (TOI brain ) and splanchnic (TOIabdo) regions will be measured using NIRS and the values reported as CSOR (TOIabdo/TOI brain). Measurements will be continuously recorded and data points obtained for 30 minute periods at baseline or T0 (prior to PRBC transfusion), and every hour during the RBC transfusion (T1, T2, T3 and T4)</description>
  </other_outcome>
  <other_outcome>
    <measure>Mesenteric rSO2</measure>
    <time_frame>53 hrs</time_frame>
    <description>To determine whether alterations in mesenteric rSO2 can predict the development of NEC in VLBW infants.&#xD;
For this aim, TOI and CSOR will be measured every 3 hours for 30 minute periods in the first 48 hours following RBC transfusion (T5 to T16)(Table 1). By obtaining measurements during this time frame, we intend to capture the period of greatest susceptibility to develop NEC in this population.</description>
  </other_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">12</enrollment>
  <condition>Anemia of Prematurity</condition>
  <condition>Necrotizing Enterocolitis</condition>
  <arm_group>
    <arm_group_label>Infants requiring PRBCs</arm_group_label>
    <description>Premature infants who require PRBCs for anemia that is not related to sepsis, surgery, NEC or immunologic abnormalities.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Premature infants admitted into the University of Utah (UUMC), Primary Children's Medical&#xD;
        Center (PCMC) and Intermountain Medical Center's (IMC) Neonatal Intesive Care Unit (NICUs)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Inpatient in NICU at UUMC, PCMC, or IMC&#xD;
&#xD;
          -  Gestational age at birth ≤ 32 weeks&#xD;
&#xD;
          -  Birth weight ≤ 1500 grams&#xD;
&#xD;
          -  Age ≤ 12 weeks of life&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Lack of parental consent&#xD;
&#xD;
          -  Multiple congenital anomalies&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>12 Weeks</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Susan Wiedmeier, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Utah</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mariana Baserga, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Utah</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Intermountain Medical Center</name>
      <address>
        <city>Murray</city>
        <state>Utah</state>
        <zip>84107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah Hospital</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84108</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Primary Children's Medical Center</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Horbar JD, Badger GJ, Carpenter JH, Fanaroff AA, Kilpatrick S, LaCorte M, Phibbs R, Soll RF; Members of the Vermont Oxford Network. Trends in mortality and morbidity for very low birth weight infants, 1991-1999. Pediatrics. 2002 Jul;110(1 Pt 1):143-51. doi: 10.1542/peds.110.1.143.</citation>
    <PMID>12093960</PMID>
  </reference>
  <reference>
    <citation>Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, Verter J, Temprosa M, Wright LL, Ehrenkranz RA, Fanaroff AA, Stark A, Carlo W, Tyson JE, Donovan EF, Shankaran S, Stevenson DK. Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics. 2001 Jan;107(1):E1. doi: 10.1542/peds.107.1.e1.</citation>
    <PMID>11134465</PMID>
  </reference>
  <reference>
    <citation>Stoll BJ. Epidemiology of necrotizing enterocolitis. Clin Perinatol. 1994 Jun;21(2):205-18. doi: 10.1016/S0095-5108(18)30341-5.</citation>
    <PMID>8070222</PMID>
  </reference>
  <reference>
    <citation>Mally P, Golombek SG, Mishra R, Nigam S, Mohandas K, Depalhma H, LaGamma EF. Association of necrotizing enterocolitis with elective packed red blood cell transfusions in stable, growing, premature neonates. Am J Perinatol. 2006 Nov;23(8):451-8. doi: 10.1055/s-2006-951300. Epub 2006 Sep 28.</citation>
    <PMID>17009195</PMID>
  </reference>
  <reference>
    <citation>Christensen RD, Lambert DK, Henry E, Wiedmeier SE, Snow GL, Baer VL, Gerday E, Ilstrup S, Pysher TJ. Is &quot;transfusion-associated necrotizing enterocolitis&quot; an authentic pathogenic entity? Transfusion. 2010 May;50(5):1106-12. doi: 10.1111/j.1537-2995.2009.02542.x. Epub 2009 Dec 29.</citation>
    <PMID>20051059</PMID>
  </reference>
  <reference>
    <citation>Josephson CD, Wesolowski A, Bao G, Sola-Visner MC, Dudell G, Castillejo MI, Shaz BH, Easley KA, Hillyer CD, Maheshwari A. Do red cell transfusions increase the risk of necrotizing enterocolitis in premature infants? J Pediatr. 2010 Dec;157(6):972-978.e1-3. doi: 10.1016/j.jpeds.2010.05.054. Epub 2010 Jul 21.</citation>
    <PMID>20650470</PMID>
  </reference>
  <reference>
    <citation>Blau J, Calo JM, Dozor D, Sutton M, Alpan G, La Gamma EF. Transfusion-related acute gut injury: necrotizing enterocolitis in very low birth weight neonates after packed red blood cell transfusion. J Pediatr. 2011 Mar;158(3):403-9. doi: 10.1016/j.jpeds.2010.09.015. Epub 2010 Nov 10.</citation>
    <PMID>21067771</PMID>
  </reference>
  <reference>
    <citation>Singh R, Visintainer PF, Frantz ID 3rd, Shah BL, Meyer KM, Favila SA, Thomas MS, Kent DM. Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants. J Perinatol. 2011 Mar;31(3):176-82. doi: 10.1038/jp.2010.145. Epub 2011 Jan 27.</citation>
    <PMID>21273983</PMID>
  </reference>
  <reference>
    <citation>El-Dib M, Narang S, Lee E, Massaro AN, Aly H. Red blood cell transfusion, feeding and necrotizing enterocolitis in preterm infants. J Perinatol. 2011 Mar;31(3):183-7. doi: 10.1038/jp.2010.157. Epub 2011 Jan 20.</citation>
    <PMID>21252964</PMID>
  </reference>
  <verification_date>May 2015</verification_date>
  <study_first_submitted>November 22, 2012</study_first_submitted>
  <study_first_submitted_qc>November 22, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 28, 2012</study_first_posted>
  <last_update_submitted>May 1, 2015</last_update_submitted>
  <last_update_submitted_qc>May 1, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">May 5, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>gut reperfusion injury</keyword>
  <keyword>blood transfusions</keyword>
  <keyword>premature infants</keyword>
  <keyword>anemia</keyword>
  <keyword>regional oxygen saturations</keyword>
  <keyword>necrotizing enterocolitis</keyword>
  <keyword>mesenteric oxygenation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Enterocolitis</mesh_term>
    <mesh_term>Enterocolitis, Necrotizing</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01735552
org study id: 51050
nct id: NCT01735552
lead sponsor: 
has dmc: No
Despite many advances in neonatal care, necrotizing enterocolitis (NEC) remains a leading
      cause of morbidity and mortality among premature infants. NEC is the most common
      life-threatening gastrointestinal emergency encountered in the neonatal intensive care unit,
      affecting between 3.8% and 13% of very low birthweight (VLBW) infants (1-3). More recently
      interest has intensified regarding the possible association between "elective" red blood cell
      (RBC) transfusions in premature infants and the subsequent development of NEC (4-9). On a
      physiological basis, a few explanations for transfusion-associated NEC have been proposed: 1)
      the physiological impact of anemia that can initiate a cascade of events leading to
      ischemic-hypoxemic mucosal gut injury predisposing to NEC [10]; and 2) increased splanchnic
      blood flow following RBC transfusion leading to reperfusion injury of gut mucosa.

      Aim 1. This study will quantify inflammatory cytokine profiles in anemic infants cared for in
      the NICU prior to and after transfusion with packed red blood cells (PRBC), as dictated by
      current clinical guidelines for treatment of anemia, and prospectively assess for clinical
      signs and symptoms of NEC following each transfusion event.

      Aim 2. Polymorphonuclear leukocytes (PMNs) isolated from the pre- and post-transfusion blood
      samples will be assessed in vitro for neutrophil extracellular traps (NET) formation.

      Aim 3. A) To determine whether significant anemia preceding a RBC transfusion is associated
      with impaired intestinal oxygenation, and whether a RBC transfusion temporarily increases
      splanchnic oxygenation. We postulate that the CSOR will be low (<0.75) at baseline
      measurement in infants with hemodynamically significant anemia, and that RBC transfusion will
      temporarily increase intestinal perfusion in that particular group of babies.

      B) To determine whether alterations in mesenteric regional oxygenation saturation(rSO2) can
      predict the development of NEC in VLBW infants. We hypothesize that overall
      cerebro-splanchnic oxygenation ratio (CSOR) values will be significantly lower among very low
      birth weight (VLBW) infants that develop NEC, when compared to CSOR values obtained in
      infants that do not develop NEC following RBC transfusion.
observational model: Case-Only
time perspective: Prospective
measure: Serum cytokine content
time frame: 6 hrs
description: Plasma samples will be analyzed for the protein content of 13 different cytokines via a multiplexed sandwich capture assay performed at the ARUP Institute for Experimental and Clinical Pathology. The cytokines and chemokines assayed will include: CD40 ligand, interferon-gamma, interleukin-10, interleukin-12, interleukin-13, interleukin-1-β, interleukin-2, interleukin-2-receptor, interleukin-4, interleukin-5, interleukin-6, IL-8, and Tumor Necrosis Factor-alpha. In addition, we will assay components of the complement pathway including: total hemolytic complement, C3a, C5a, and FAB fragments in the alternative complement pathway. Cytokine protein levels before and after transfusion will be compared to each other and to the PRBC sample cytokine content.
measure: Assessment of NET formation
time frame: 6 hrs
description: PMNs will be isolated from the participant blood samples following removal of the plasma via positive immunoselection. They will then be stimulated in vitro with NET-inducing stimuli such as lipopolysaccharide or platelet-activating factor for 1 hour under standard conditions and assayed for NET formation both qualitatively via confocal microscopy and quantitatively via histone H3 supernatant content as determined by ELISA and/or western blotting.
measure: Tissue oxygenation indexes (TOI) of cerebral (TOI brain ) and splanchnic (TOIabdo) regions
time frame: 53 hrs
description: Tissue oxygenation indexes (TOI) of cerebral (TOI brain ) and splanchnic (TOIabdo) regions will be measured using NIRS and the values reported as CSOR (TOIabdo/TOI brain). Measurements will be continuously recorded and data points obtained for 30 minute periods at baseline or T0 (prior to PRBC transfusion), and every hour during the RBC transfusion (T1, T2, T3 and T4)
measure: Mesenteric rSO2
time frame: 53 hrs
description: To determine whether alterations in mesenteric rSO2 can predict the development of NEC in VLBW infants.
For this aim, TOI and CSOR will be measured every 3 hours for 30 minute periods in the first 48 hours following RBC transfusion (T5 to T16)(Table 1). By obtaining measurements during this time frame, we intend to capture the period of greatest susceptibility to develop NEC in this population.
arm group label: Infants requiring PRBCs
description: Premature infants who require PRBCs for anemia that is not related to sepsis, surgery, NEC or immunologic abnormalities.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: 12 Weeks
healthy volunteers: No
last name: Susan Wiedmeier, MD
role: Principal Investigator
affiliation: University of Utah
last name: Mariana Baserga, MD
role: Principal Investigator
affiliation: University of Utah
facility: 
facility: 
facility: 
country: United States
citation: Horbar JD, Badger GJ, Carpenter JH, Fanaroff AA, Kilpatrick S, LaCorte M, Phibbs R, Soll RF; Members of the Vermont Oxford Network. Trends in mortality and morbidity for very low birth weight infants, 1991-1999. Pediatrics. 2002 Jul;110(1 Pt 1):143-51. doi: 10.1542/peds.110.1.143.
PMID: 12093960
citation: Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, Verter J, Temprosa M, Wright LL, Ehrenkranz RA, Fanaroff AA, Stark A, Carlo W, Tyson JE, Donovan EF, Shankaran S, Stevenson DK. Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics. 2001 Jan;107(1):E1. doi: 10.1542/peds.107.1.e1.
PMID: 11134465
citation: Stoll BJ. Epidemiology of necrotizing enterocolitis. Clin Perinatol. 1994 Jun;21(2):205-18. doi: 10.1016/S0095-5108(18)30341-5.
PMID: 8070222
citation: Mally P, Golombek SG, Mishra R, Nigam S, Mohandas K, Depalhma H, LaGamma EF. Association of necrotizing enterocolitis with elective packed red blood cell transfusions in stable, growing, premature neonates. Am J Perinatol. 2006 Nov;23(8):451-8. doi: 10.1055/s-2006-951300. Epub 2006 Sep 28.
PMID: 17009195
citation: Christensen RD, Lambert DK, Henry E, Wiedmeier SE, Snow GL, Baer VL, Gerday E, Ilstrup S, Pysher TJ. Is "transfusion-associated necrotizing enterocolitis" an authentic pathogenic entity? Transfusion. 2010 May;50(5):1106-12. doi: 10.1111/j.1537-2995.2009.02542.x. Epub 2009 Dec 29.
PMID: 20051059
citation: Josephson CD, Wesolowski A, Bao G, Sola-Visner MC, Dudell G, Castillejo MI, Shaz BH, Easley KA, Hillyer CD, Maheshwari A. Do red cell transfusions increase the risk of necrotizing enterocolitis in premature infants? J Pediatr. 2010 Dec;157(6):972-978.e1-3. doi: 10.1016/j.jpeds.2010.05.054. Epub 2010 Jul 21.
PMID: 20650470
citation: Blau J, Calo JM, Dozor D, Sutton M, Alpan G, La Gamma EF. Transfusion-related acute gut injury: necrotizing enterocolitis in very low birth weight neonates after packed red blood cell transfusion. J Pediatr. 2011 Mar;158(3):403-9. doi: 10.1016/j.jpeds.2010.09.015. Epub 2010 Nov 10.
PMID: 21067771
citation: Singh R, Visintainer PF, Frantz ID 3rd, Shah BL, Meyer KM, Favila SA, Thomas MS, Kent DM. Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants. J Perinatol. 2011 Mar;31(3):176-82. doi: 10.1038/jp.2010.145. Epub 2011 Jan 27.
PMID: 21273983
citation: El-Dib M, Narang S, Lee E, Massaro AN, Aly H. Red blood cell transfusion, feeding and necrotizing enterocolitis in preterm infants. J Perinatol. 2011 Mar;31(3):183-7. doi: 10.1038/jp.2010.157. Epub 2011 Jan 20.
PMID: 21252964
responsible party type: Sponsor
mesh term: Enterocolitis
mesh term: Enterocolitis, Necrotizing