WithHolding Enteral Feeds Around Blood Transfusion (International)

Study Overview
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Brief Summary
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The WHEAT International trial is a comparative effectiveness trial exploring whether withholding enteral feeds around the time of blood transfusion in very premature infants (<30 weeks) will reduce the occurrence of Necrotizing Enterocolitis (NEC). Currently both continued feeding and withholding feeding are approved care practices. The current study will randomize infants from Neonatal Intensive Care Units (NICUs) across Canada and the United Kingdom (UK) into one of the two care approaches (withholding or continued feeds) to determine if any significant outcomes are found.

Detailed Description
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BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating disease that affects mostly the intestine of premature infants. The wall of the intestine is invaded by bacteria, which cause local infection and inflammation that can ultimately destroy the wall of the bowel (intestine). NEC is among the most potentially devastating neonatal diseases and has a mortality of up to 33%, the most severe form (requiring surgery or resulting in death) affects about 5% of infants born at less than 30 gestational weeks; survivors are at high risk of long-term health and developmental problems. Prevention of NEC has been identified as one of the most important research uncertainties in the field of preterm birth. A temporal association between red cell transfusion and the subsequent development of the disease is well described. This 'transfusion-associated NEC' may also be more severe with higher mortality. Very preterm or extremely low birth weight infants are among the most frequently transfused patients: between 56% and 90-95% have at least one transfusion, and those transfused received an average of 5 transfusions in their neonatal stay. Withholding milk feeds during red cell transfusion may reduce the risk of NEC by decreasing postprandial mesenteric ischemia but there may be harmful effects of pausing enteral feeds. However, due to a lack of good quality evidence, there is no consensus regarding the optimal feeding strategy during a blood transfusion. Both comparator pathways of care are standard practice in Canada and the UK; the WHEAT trial is a comparative effectiveness trial. The two care pathways that will be compared are: Withholding Feeds Around Transfusion: All enteral feeds will be discontinued (the infant will be placed nil by mouth) for 4 hours prior to packed red cell transfusion, during the packed red cell transfusion and until 4 hours post packed red cell transfusion. Continuing Feeds Around Transfusion: Enteral feeds will continue to be given prior, during and after the packed red cell transfusion, in the manner in which they were being given prior to the decision to transfuse. Infants will remain allocated to the same care pathway until 34(+6) weeks(+days) gestational age.

Official Title
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The WHEAT International Trial: WithHolding Enteral Feeds Around Red Cell Transfusion to Prevent Necrotizing Enterocolitis in Preterm Neonates: an International, Multi-centre, Randomized Controlled Trial

Conditions
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Necrotizing Enterocolitis

Intervention / Treatment
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* Other: Withholding feeds around transfusion
* Other: Continued feeds around transfusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Preterm birth at <30+0 gestational weeks + days Exclusion Criteria: Parent(s) opt-out of trial participation. Packed red cell transfusion with concurrent enteral feeds prior to enrolment. (Infants who have received a packed red cell transfusion while nil-by-mouth are eligible; buccal colostrum will not be counted as enteral feeding). Infants where enteral feeding is contraindicated in the first 7 days after birth [e.g. Major congenital abnormality of the gastrointestinal tract (GIT)]. Previous episode of NEC or spontaneous intestinal perforation (SIP) prior to first packed cell transfusion.

Ages Eligible for Study
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Maximum Age: 30 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The WHEAT trial is a pragmatic, randomized, controlled, unblinded, international, multicentre, parallel-group superiority trial comparing two clinical care pathways.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Withholding feeds around transfusion<br>All enteral feeds will be discontinued (the infant will be placed nil by mouth) for 4 hours prior to packed red cell transfusion, during the transfusion and until 4 hours post transfusion. During this period, hydration and blood glucose will be maintained according to local practice, commonly by providing parenteral nutrition or intravenous dextrose. Four hours after the red cell transfusion has finished, feeds will be recommenced to how they were being received prior to the decision to transfuse. This duration of withholding feeds will follow the approach used in other trials and observational studies, and identified as the most acceptable in a survey of UK neonatal units. It gives time for milk in the small bowel to transit into the large bowel before the transfusion and for the circulation to stabilize after the transfusion before milk feeds given into the stomach pass through into the small intestine. | Other: Withholding feeds around transfusion<br>* Withholding enteral feeds for preterm infants (<30 weeks) around the time of blood transfusions to determine if any impact on the development and/or severity of Necrotizing Enterocolitis.<br>|
| Active Comparator: Continuing feeds around transfusion<br>Enteral feeds will continue to be given prior, during and after the packed red cell transfusion, in the manner in which they were being given prior to the decision to transfuse. Infants will remain allocated to the same care pathway until 34(+6) weeks(+days) gestational age. | Other: Continued feeds around transfusion<br>* Continued enteral feeds<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NEC Stage II | NEC stage II or more after the first transfusion (modified Bell staging criteria) - Clinical signs and symptoms plus pneumatosis or portal/hepatic air diagnosed by x-ray or other imaging techniques | From randomization to 40 weeks postmenstrual age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severe NEC | Histologically or surgically confirmed or recorded on the death certificate. These infants will be identified as described in Battersby et al. which will include infants recorded as being transferred for surgery. | From randomization to 40 weeks postmenstrual age | 
| Death | All-cause mortality | From randomization to 40 weeks postmenstrual age | 
| Late onset sepsis | Culture positive sepsis, onset after 72 hours of life | From randomization to 40 weeks postmenstrual age | 
| Number of days with a central venous line in situ | Number of days with a central venous line in situ | From birth to date of discharge home | 
| Number of central line associated bloodstream infections | Includes laboratory-confirmed bloodstream infection and clinical sepsis | From randomization to 40 weeks postmenstrual age | 
| Duration of any parenteral nutrition in days | Duration of any parenteral nutrition in days | From birth to 40 weeks postmenstrual age | 
| Growth | Weight and head circumference z score. | At date of discharge home | 
| Spontaneous Intestinal Perforation | Histologically or surgically confirmed or recorded in the death certificate. | From randomization to 40 weeks postmenstrual age | 
| Duration of hospital stay | Total duration of neonatal care in days including all levels of care (intensive care, high dependency care, special care and ordinary care) | From birth to date of discharge home | 
| Bronchopulmonary Dysplasia (BPD)/Chronic Lung Disease | Requiring respiratory support at 36 weeks gestation | At 36 weeks postmenstrual age | 
| Retinopathy of prematurity (ROP) | ROP requiring treatment | From randomization to 40 weeks postmenstrual age | 
| Severe Brain Injury | Intraventricular haemorrhage (IVH) grade 3 or 4 or cystic periventricular leukomalacia (PVL) | At 40 weeks postmenstrual age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Comparative Effectiveness Trial, Necrotizing Enterocolitis, Premature Infants, Blood Transfusion, Withholding enteral feeds