Aim of the study
Primary outcome is to evaluate the effectiveness of OMT in reducing LOS in a sample of premature infants.
Secondary outcome of the study is to evaluate the difference in daily weight gain, number of episodes of vomit and regurgitation, stooling, use of enema, time to full enteral feeding (breastfeeding and/or bottle) and NICU costs.
Interventional, multicentre nationwide single-blinded randomised controlled trial. Preterm infants entering the trial will either receive routine medical care plus osteopathic evaluation and treatment or routine medical care plus osteopathic evaluation only ().
Flow chart describing, recruitment randomisation data collection and analysis of the study.
Patients will be recruited from three Italian secondary and tertiary NICUs at the public hospital in Pescara, Macerata and Monza.
The three participating NICUs are located throughout Italy in urban regions with catchment areas of about 40 000–150 000 inhabitants. Principal investigators of the participating NICUs are neonatologists and osteopaths with at least 5 years of experience in osteopathic treatments in NICU and specialised neonatal osteopathic education.
Participants who meet the following inclusion criteria are considered eligible for the trial: male and female preterm infants entering the NICUs in the period between 1 July 2012 and 30 June 2013, preterms born in the same hospital of the referred NICU and free of medical complications and parents’ or legal guardians’ written informed consent.
Subjects presenting the following clinical conditions are excluded:
- Gestational age <29 weeks
- Gestational age >37 weeks
- First OMT performed after 14 days from birth
- Genetic disorders
- Congenital disorders
- Cardiovascular abnormalities
- Proven or suspected necrotised enterocolitis with or without gastrointestinal perforation
- Proven or suspected abdominal obstruction
- Pre/post surgery patients
- Newborn from an HIV seropositive/drug-addicted mother
- Respiratory disorders
- Transferred to/from other hospital
- Admitted for preterminal comfort care (defined as neither intubation nor cardiorespiratory resuscitation)
All patients entering the study are sequentially allocated to the experimental and control arms using R (R core team, Vienna, Austria), an open source statistical software, as computer random number generator.18
The type of randomisation procedure is permuted-block (ratio 1:1).
The process of randomisation is performed in the coordinating centre.
Investigators will be grouped into three:
- 1. Consultant performing the randomisation
- 2. Osteopaths performing the evaluation
- 3. Osteopaths performing the evaluation and treatment
Consultant performing the randomisation
An information technology consultant will be responsible for randomisation prior to the arrival of the osteopaths to the NICU.
Osteopaths performing the evaluation
Osteopaths in this group will perform the osteopathic evaluation in all infants entering the trial, with no knowledge about patients’ allocation.
The osteopathic evaluation will be performed in the absence of the ‘osteopaths performing the evaluation and treatment’.
Osteopaths performing the evaluation and treatment
‘Osteopaths performing the evaluation and treatment’ will perform an osteopathic evaluation and treatment of preterm infants from group ‘A’.
Intervention provided to the trial
Patients from experimental and control groups will receive routine medical care.
After study enrollment, all patients are sampled in group A and group B.
Group A (OMT): patients under usual medical care plus osteopathic treatment
Patients from this group will receive osteopathic care as follows: two treatments weekly for the entire LOS in the unit. Patients from group A will also receive an osteopathic evaluation from the ‘osteopaths performing the evaluation’.
Osteopathic treatments will only be applied to patients from group A and will be performed only by the ‘osteopaths performing the evaluation and treatment’, not involved in the study design, data entry and statistical analysis.
Each OMT session involve the structural examination and specific manipulative procedures.
In newborns the structural exam is usually performed with the child lying down in the open crib or incubator. Diagnostic criteria for somatic dysfunction are focused on tissue texture abnormalities, areas of asymmetry and misalignment of bony landmarks and the quality of motion, its balance and organisation.
The second part of the OMT session is characterised by the use of a variety of therapeutic manual techniques, addressed to increase range of motion and resolve the somatic dysfunctions diagnosed.
Techniques to be used are in line with the benchmarks for osteopathic treatment available in the medical literature and are limited to myofascial release, balanced ligamentous/membranous tension, indirect fluidic and v-spread. The whole session will last 30 min, 10 min for evaluation and 20 min for treatment.
Group B (no OMT): control group
Following the same schedule as for group A, patients from group B will receive usual medical care and osteopathic evaluation only. The osteopathic evaluation will last for 10 min. To maintain blinding of NICU personnel to patients’ allocation, the following 20 min osteopaths will keep their position close to the incubator or bed without touching the infant.
Osteopathic service will be provided twice a week, on Tuesdays and Fridays.
In case of critical preterm health conditions (ie, acute infections, peracute emergency care) or supplemental neonatal medical screening during the osteopathic service, the aforementioned intervention can be temporally stopped for a given trial participant. The infant will neither be evaluated or treated. This is in line with hospital safety procedures and primary care priority intervention.
Allocation concealment and blinding
NICU staffs are unaware of the study design and outcomes.
NICU staffs are blinded to patients’ allocation, since all infants will be touched by osteopaths from group A and B.
Data entering and data export
Data collection will be performed using an ad hoc locally developed software called EBOM-GCCN.
EBOM-GCCN dataset is an informatics tool that improves the efficiency and accuracy of data and has been developed to assist neonatologists, nurses and osteopaths in daily patients’ management.
The software consists of three sections:
- Section 1: Intended for use by neonatologists and nurses for recording patients’ general details and all clinical information;
- Section 2: Intended for use by ‘osteopaths performing the evaluation and treatment’;
- Section 3: Intended for use by ‘osteopaths performing the evaluation’.
Records in sections 1, 2 and 3 are exclusively and respectively accessible to NICU staff, ‘osteopaths performing the evaluation and treatment’ and ‘osteopaths performing the evaluation’.
Nursing and medical records will be collected daily by the NICU staff, from the time the infants enter the unit to the time of discharge.
Osteopathic records will be collected twice weekly when the osteopathic service will be provided. ‘Osteopaths performing the evaluation and treatment’ will collect data in relation to the structural examination and the techniques applied, while the ‘osteopaths performing the evaluation’ will only collect data for the structural examination.
Data export will take place at the end of the study by the statistician from the coordinating centre, European Institute for Evidence-Based Osteopathic Medicine (EBOM).
To evaluate the effect of the treatment, standard measurements will be recorded. Data will be collected at the baseline (entry time, T0), every time the osteopathic service is provided and at the end of the stay in the unit (discharge time, T1). An expected average period of 4 weeks has been considered.
The following measurements will be included for the primary and secondary outcomes.
Primary outcome: LOS
LOS will be used as primary outcome and is measured as the mean difference in days between T1 and T0.
According to international guidelines, the following physiological conditions are required for discharge: maintenance of body heat at room temperature, coordinated sucking, swallowing and breathing while feeding; sustained pattern of weight gain; stability of cardiorespiratory function (no episodes of apnoea/bradycardia for 2–5 days, free of supplemental oxygen support).8
Secondary outcome measurements include the following parameters:
- Daily weight gain, referred to as the net weight variation per day expressed in grams;
- Episodes of vomit, the number of vomits per day;
- Episodes of regurgitation, the number of regurgitations per day;
- Episodes of stooling, the number of stools per day;
- Use of enema, the number of enemas used per day;
- Time to reach full enteral feeding, the number of days before autonomous feeding is achieved;
- NICU costs, calculated as NICU daily newborn expenses, according to local authorities, multiplied by the newborn's LOS. Costs will be estimated in terms of Euros per day;
- Side effects of treatment (osteopathy and clinical procedures).
In addition to these measurements, sociodemographic and clinical data will be collected apart from the following data:
- 1. Newborn's data: gender, gestational age, weight at birth and at entry, height, head circumference at birth, route, type and length of delivery, diagnosis at T0 and T1 and associated pathologies;
- 2. Mother's data: age, ethnicity, body mass index (BMI), nationality, number of previous pregnancies, clinical medical condition during pregnancy and concurrent pathologies;
- 3. Father's data: age, ethnicity, BMI, nationality, concurrent pathologies.
All calculations will be performed at the coordinating centre, EBOM.
Statistical analyses will take into account the intention-to-treat analysis. Missing data will be handled using last observation carried forward (LOCF) imputation technique. Arithmetic means and standard deviation will be used for the general characteristics of the study population. Univariate statistical tests will be performed to compare the experimental group and control group at the baseline. A generalised linear model, linear regression, will be considered to study the independent effect of OMT on primary endpoint and secondary endpoints, taking into account all possible confounders. The significance level will be at α=0.01. Differences between the groups will be presented as mean with 95% CI or in categories with OR for categorical data.
The statistical programme in use for randomisation and data analyses is R.18
Sample size calculation used an effective size of 0.3 calculated from previous studies, considering a mean difference of 4 days between experimental and control group and an SD of 14. The statistical power is set at 0.90 and an α-level equal to 0.01. This produces a sample size of 333 per group. To prevent loss of power, the sample size is increased up to 345 subjects per group. The whole sample (N=690) is then divided, with a final result of N=230 preterm infants for each NICU. A longer period of study enrollment has been considered a strategy to achieve the estimated sample size.
The coordinating centre EBOM consists of an executive division, President and Vice President, an administration office, a group of researchers, an information technology consultant and a senior biostatistician.
The coordinating centre collaborates with the A.I.O.T.—Accademia Italiana Osteopatia Tradizionale.