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Dose response Study


Neuro-
developmental
study


Respiratory study

Economic evaluation study

Views of participants in trials

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


Sub-studies are also in place to consider other developmental and respiratory outcomes,
cost-effectiveness, dose response of preterm babies, respiratory function and views of trial
participants.


Dose Response Study 

At the 1st INNOVO UK Collaborators’ meeting in January 1997, many different opinions about the correct dose of inhaled nitric oxide to use for the trial were expressed. In the face of this (collective) uncertainty, and very little useful information from the literature, a decision was taken by the Trial Steering Committee to conduct a dose-response study to be carried out on preterm (<34 weeks) babies receiving nitric oxide (both outside and within the trial) in those centres willing to participate in this study.  

Based on the discussion at the Collaborators’ meeting and the relevant literature, four doses, given in random order, were compared: 5, 10, 20 and 40 parts per million (ppm). Each dose will be of 15 minutes duration, with a period of at least 5 minutes without nitric oxide between each of the four doses to allow the blood gases to return to baseline.

Four hospitals(Leicester Royal Infirmary,Rosie Maternity Hospital Cambridge, Royal Maternity Hospital Belfast, and Simpson Maternity Pavilion, Edinburgh)entered preterm babies into this study and the results are soon to be published. [see publications] Ahluwalia ,J; Tooley,J; Cheema,I; Sweet,DG; Curley,AE; Halliday,HL; Field,D; Al'malik H; Annamalai,S; Midgley,P; Hardy,P; Tomlin,K; Elbourne, Diana; A dose response study of inhaled nitric oxide in hypoxic respiratory failure in preterm infants. Early Human Development, In Press

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Respiratory follow-up

Introduction

In an attempt to address concerns that the administration of inhaled nitric oxide (INO) during the neonatal period may be associated with detrimental effects on the developing lung, a respiratory follow-up was as part of The INNOVO Trial. This involved:-

a) The documentation of relevant information regarding the occurrence of respiratory problems during the first year of life using a
questionnaire to be administered to the families of all infants at the time of their one-year (corrected) paediatric assessment, together    with relevant information gleaned from the health economics survey

b) By respiratory function tests, plus a more detailed questionnaire, in a sub-group of infants at approximately one year of age.

Aims

The aims of this study were to:-

                1. Compare the occurrence of respiratory problems
                    during the first year of life

2. Compare respiratory function in infants
    who have and have not received INO as 
    part of their treatment for respiratory failure
    during the neonatal period.

Protocol

A set of respiratory related questions to document the occurrence of respiratory problems during the first year of life in those who did and did not receive INO has been incorporated into the questionnaire to be administered to all infants at their one year check up by their local paediatrician. A few additional questions to elicit background information, essential for the interpretation of the answers (e.g. exposure to environmental tobacco smoke, family history of asthma, etc), have been asked. Some simple relevant questions have been incorporated into the health economics questionnaire.

Detailed respiratory function tests have been performed at either the Institute of Child Health, London or Leicester Royal Infirmary using standardised methods of data collection and analysis. Infants have been recruited to this part of the project unless either their GP or paediatrician feel that it was inappropriate for them to travel to the test centre. Travel expenses were provided. On arrival at the test centre, a brief questionnaire was administered and the infant was examined clinically before being sedated orally with chloral hydrate. The lung function tests were performed once the infant has fallen asleep. Resting lung volume and forced expiratory flows will be assessed to obtain baseline measurements of lung and airway function. In those with signs of diminished baseline airway function, a dose of salbutamol (bronchodilator) is administered before repeating the lung function measurements. Results were cross-analysed between the test centres blinded to the infants’ management status at birth. Parents, their GP and their paediatrician were notified of the results. 

Further information regarding this study can be obtained from:

Professor Janet Stocks
Professor of Respiratory Physiology
Portex Anaesthesia, Intensive Care & Respiratory Medicine Unit
Institute of Child Health
30 Guilford Street
LONDON WC1N 1EH

Tel: 020 7242 9789 ext 2382
E-mail: j.stocks@ich.ucl.ac.uk

Dr Caroline Beardsmore
Lecturer in Respiratory Physiology
Department of Child Health
Clinical Sciences Building
Leicester Royal Infirmary
PO Box 65
Leicester LE2 7LX

Tel: 0116 258 6769
E-mail: csb@le.ac.uk

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Economic Evaluation

In the economic evaluation for The INNOVO Trial, information on the clinical effectiveness of the policies of adding or not adding nitric oxide (NO) to the ventilator gases administered to babies in The INNOVO Trial will be related to the costs associated with the alternative policies, using a cost-effectiveness framework.

Given an element of fixed costs, INO will be cheaper when used more intensively. It is likely, however, that the bulk of the costs will be for consumables. It is important to assess the fixed and variable costs, so as to be able to relate the results to use in different circumstances.

Although it is necessary to assess the costs of inhaled NO (INO) itself, the costs of the resulting benefits also depend on the other health care activities that are affected by its use. For example, if successful treatment affects the length of stay in hospital, then the overall difference in costs may be less than, more than, or the same as the cost of INO itself. The costing therefore has to take into account such consequential costs.

Reflecting the two main clinical outcomes being considered, the costing concentrates on the period up to discharge from hospital, and the first year of life.

     1.  Data about health service usage during the first hospital stay were collected
          on the trial datasheets. The indirect and direct costs of this stay are based on those
          derived from previous related studies.

    2.  Information about health service usage and costs to parents between discharge
          home and one year of age (corrected) were ascertained from questionnaire(s)
          sent to the parents at home. These questionnaires were from the Data
          Co-ordinating Centre at 6 monthly intervals. This repeated sampling at fixed points in
          (chronological) time allows some information about each four-week time period
          between discharge and one year of age (corrected) from a sample of parents. Some
          parents will receive only one such questionnaire between the time their baby is
          discharged home and one year of age (corrected), and no parent will receive more
          than two questionnaires. The questionnaire(s) asks for background information about
          the families (this will only be asked on the first such questionnaire the family receive)
          and hospital admissions (from first discharge from hospital or from the time of the
          previous questionnaire).  To aid recall, the questionnaires ask about use of primary
          health services within the previous four week period only.

 

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 Neurodevelopmental

The primary outcomes in this trial include death and severe disability as assessed at the age of one year (corrected), so follow-up is a key issue in The INNOVO Trial.

The agreed definition of severe disability at one year of age (corrected) is defined as no/minimal head control or inability to sit unsupported, or no/minimal responses to visual stimuli, as these have been found to be equivalent to a Developmental Quotient (DQ) of < 50.

When the baby was discharged home, the parents were given a letter about the follow-up. The nurse co-ordinator in each centre is responsible for ensuring that parents receive this information, and there is a box on the discharge datasheet which should be ticked when the letter has been given.

When the baby was about 11 months (corrected age), the Data Co-ordinating Centre writes to the local paediatrician caring for the baby, sending him/her a brief questionnaire to complete at the routine follow-up clinic visit at one year of age (corrected). This questionnaire asked about impairment and disability (neuromotor, vision, hearing, and development); respiratory problems (symptoms, lung and airway growth, airway reactivity); seizures; reduced growth.

All UK children will be flagged on the National Health Service Central Register.

The neurodevelopmental follow up has been developed in close collaboration with members of the respiratory follow-up group. See publications.

Field D, Elbourne D, Truesdale A, Grieve R, Hardy P, Fenton A C et al. Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infants with severe respiratory failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005; 115(4): 926-36.

Field D; Elbourne D; Hardy P; Fenton AC; Ahluwalia J; Halliday HL; Subhedar N; Heinonen K; Aikio O; Grieve R; Truesdale A; Tomlin K; Normand C; Stocks J; on behalf of the INNOVO Trial Collaborating Group.Title: Neonatal ventilation with INhaled Nitric Oxide versus Ventilatory support withOut inhaled nitric oxide for infants with severe respiratory failure born at or near term: The INNOVO multicentre randomised controlled trial
(ISRCTN 17821339) Biology of the Neonate, In Press

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Views of participants

Rapid changes in the scientific basis of research in health care such as the use of randomized controlled trials (RCTs) affect both patients and professional caregivers. Recent qualitative studies have addressed a number of aspects of RCT participation from the perspective of parents of critically ill babies involved in the neonatal ECMO trial. Consent for RCTs in life-threatening circumstances is inevitably a difficult area, and the research clearly indicated that there was often confusion about the nature and purpose of the trial, the use of randomization and the unevaluated status of the experimental treatment

In the INNOVO trial, this work is being extended in some centres in four main ways:

  • by tape-recording some informed consent encounters (in which parents are asked about participating in the trial, and consent is either given or withheld), to observe what actually happens;

  • by interviewing parents in a further trial i.e. the INNOVO trial (and other trials where relevant), to provide a more generalizable dataset;

  • by interviewing more parents, to be more confident that the earlier findings were not due to small numbers;

  • by including bereaved parents who may have different perspectives

  • by including parents who did not give their consent to participation (refusers); and
  • by interviewing both parents and caregivers participating in the same trials, to incorporate an additional and crucial multi-dimensional perspective into the ‘equation’.

This study has provided further data to contribute to the debate about the concept and practice of informed consent. It has also highlighted the training and support needs of caregivers who carry out the potentially stressful task of recruitment to a trial. Dissemination of the research results will facilitate the introduction of methods to improve the experience of participation in trials, and to allow the development of protocols for research into other methods.

See publications

Snowdon C, Elbourne DR, Garcia J. Snap decisions: parental and professional perspectives on the speed of decisions about participation in perinatal trials. Social Science & Medicine 2006; 62 (9): 2279-90
Snowdon C (2005) Collaboration, participation and non-participation: decisions about involvement in randomised controlled trials for clinicians and parents in two neonatal trials. PhD thesis, London School of Hygiene and Tropical Medicine, University of London
Snowdon C, Elbourne DR, Garcia J. Perinatal pathology in the context of a clinical trial: a review of the literature. Arch. Dis. Child. Fetal Neonatal Ed. 2004; 89: F200-F203.
Snowdon C, Elbourne DR, Garcia J.. Perinatal pathology in the context of a clinical trial: attitudes of neonatologists and pathologists. Arch. Dis. Child. Fetal Neonatal Ed. 2004; 89: F204-F207
Snowdon C, Elbourne DR, Garcia J.. Perinatal pathology in the context of a clinical trial: attitudes of bereaved parents. Arch. Dis. Child. Fetal Neonatal Ed. 2004; 89: F208-F211
Snowdon C, Elbourne DR, Garcia J.. (2004) Embedding a qualitative approach within a quantitative framework: an example in a sensitive setting. (In) Lavender T, Edwards G and Alfirevic Z (eds) Demystifying qualitative research in pregnancy and childbirth. Quay books, London
Garcia J, Elbourne D, Snowdon C. Equipoise: a case study of the views of clinicians involved in two neonatal trials. Clinical Trials. 2004; 1 (2): 170-178

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