Transfusion-related Inflammatory Cytokine and Neutrophil Extracellular Trap Quantification in Neonates
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Purpose
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.
| Condition |
|---|
|
Anemia of Prematurity Necrotizing Enterocolitis |
| Study Type: | Observational |
| Study Design: | Observational Model: Case-Only Time Perspective: Prospective |
| Official Title: | Transfusion-related Inflammatory Cytokine and Neutrophil Extracellular Trap Quantification in Neonates. |
- Serum cytokine content [ Time Frame: 6 hrs ] [ Designated as safety issue: No ]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.
- Assessment of NET formation [ Time Frame: 6 hrs ] [ Designated as safety issue: No ]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.
- Tissue oxygenation indexes (TOI) of cerebral (TOI brain ) and splanchnic (TOIabdo) regions [ Time Frame: 53 hrs ] [ Designated as safety issue: No ]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)
- Mesenteric rSO2 [ Time Frame: 53 hrs ] [ Designated as safety issue: No ]
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.
| Estimated Enrollment: | 200 |
| Study Start Date: | June 2012 |
| Estimated Study Completion Date: | June 2014 |
| Estimated Primary Completion Date: | June 2014 (Final data collection date for primary outcome measure) |
| Groups/Cohorts |
|---|
|
Infants requiring PRBCs
Premature infants who require PRBCs for anemia that is not related to sepsis, surgery, NEC or immunologic abnormalities.
|
Eligibility| Ages Eligible for Study: | up to 12 Weeks |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
| Sampling Method: | Non-Probability Sample |
Premature infants admitted into the University of Utah (UUMC), Primary Children's Medical Center (PCMC) and Intermountain Medical Center's (IMC) Neonatal Intesive Care Unit (NICUs)
Inclusion Criteria:
- Inpatient in NICU at UUMC, PCMC, or IMC
- Gestational age at birth ≤ 32 weeks
- Birth weight ≤ 1500 grams
- Age ≤ 12 weeks of life
Exclusion Criteria:
- Lack of parental consent
- Multiple congenital anomalies
Contacts and Locations| Contact: Karen Osborne, RN | 801-213*3298 | karen.osborne@msn.com |
| United States, Utah | |
| Intermountain Medical Center | Recruiting |
| Murray, Utah, United States, 84107 | |
| Contact: Karen Osborne, RN 801-213-3298 karen.osborne@hsc.utah.edu | |
| Contact: , M.D. | |
| Sub-Investigator: Mariana Baserga, M.D. | |
| Principal Investigator: Susan Wiedmeier, MD | |
| University of Utah Hospital | Recruiting |
| Salt Lake City, Utah, United States, 84108 | |
| Contact: Karen Osborne, RN 801-213-3298 karen.osborne@hsc.utah.edu | |
| Principal Investigator: Susan Wiedmeier, MD | |
| Sub-Investigator: Mariana Baserga, MD | |
| Primary Children's Medical Center | Recruiting |
| Salt Lake City, Utah, United States, 84112 | |
| Contact: Karen Osborne, RN 801-213-3298 karen.osborne@hsc.utah.edu | |
| Principal Investigator: Susan Wiedmeier, MD | |
| Sub-Investigator: Mariana Baserga, MD | |
| Principal Investigator: | Susan Wiedmeier, MD | University of Utah |
| Principal Investigator: | Mariana Baserga, MD | University of Utah |
More Information
Publications:
| Responsible Party: | University of Utah |
| ClinicalTrials.gov Identifier: | NCT01735552 History of Changes |
| Other Study ID Numbers: | 51050 |
| Study First Received: | November 22, 2012 |
| Last Updated: | November 22, 2012 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by University of Utah:
|
gut reperfusion injury blood transfusions premature infants anemia |
regional oxygen saturations necrotizing enterocolitis mesenteric oxygenation |
Additional relevant MeSH terms:
|
Anemia Enterocolitis Anemia, Neonatal Infant, Premature, Diseases Enterocolitis, Necrotizing Hematologic Diseases |
Gastroenteritis Gastrointestinal Diseases Digestive System Diseases Intestinal Diseases Infant, Newborn, Diseases |
ClinicalTrials.gov processed this record on May 19, 2013