Clinical trial NCT02726178: Cardio-respiratory Events and Inflammatory Response After Primary Immunization in Preterm Infants
Official title: Cardio-respiratory Events and Inflammatory Response After Primary Immunization in Preterm Infants < 32 Weeks Gestational Age: A Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Complication Due to Immunization
Keywords: Apnea
bradycardia
immunization
inflammation
preterms
Lead sponsor: St. Justine's Hospital
Sponsor class: OTHER
Collaborators: name: Rennes University Hospital
First posted: 2016-04-01
Enrollment: 56
Sex: ALL
Minimum age (years): 7
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: Background: Inflammation may depress respiration in neonates. The aim of this study was to establish a link between post-immunization inflammation and cardio-respiratory events (CRE).

Methods: Randomized double-blind controlled study of infants born \<32 weeks gestation receiving the 2 months vaccine. Infants were randomized into an ibuprofen treatment group and a placebo control group. C-reactive protein (CRP) and prostaglandins E2 (PgE2) levels were assessed before and after immunization. CRE were recorded for 72 hours. Heart rate variability (HRV) was assessed by polysomnography.

Detailed description: Background: Immunization with the pentavalent vaccine Diphtheria-Tetanus-Acellular pertussis-Inactivated poliomyelitis-Haemophilus influenzae type b (DTPa-IPV-Hib) at two months of age is known to be associated with cardio-respiratory events (CRE), such as apnea and bradycardia, in 11 to 47% of preterm infants \[1,2\]

Methods: This randomized, double blinded, placebo-controlled study was conducted in the neonatal intensive care unit of Sainte-Justine University Hospital (Montreal, QC, Canada) over a period of fourteen months (February 2010 - March 2011). Study was approved by CHU Sainte-Justine institutional Ethics Committee for Clinical Studies. Written informed parental consent was obtained for all infants.

The vaccines administered were: Diphtheria-Tetanus-Acellular pertussis-Inactivated polio-Haemophilus influenzae type B (DTaP-IPV-HIB: Pediacel® 0.5ml) and the pneumococcal conjugate 10-valent vaccine (Synflorix® 0.5ml). The two vaccines were administered by nurses intramuscularly in the anterolateral region of each thigh.

On enrollment, patients were randomized by the pharmacy (investigator blinded) into two groups: the study group received oral ibuprofen (Advil® Pediatric drops for infants \< 3 months of age; Wyeth-Ayerst 40 mg/ml, DIN 2242522) 5 mg/kg/dose as recommended by the manufacturer (Ibuprofen; n=28):http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.

The control group received an oral placebo (Placebo; n=28). The placebo was prepared by the CHU Sainte-Justine pharmacy and was composed of sodium stearate 0.25g + lactose 0.5g + 15 ml of simple syrup, with a measured osmolarity of about 750 mosml/kg. The drugs were administered by nurses in an opaque syringe 30 minutes prior to immunization, and then at 8 and 16 hours following the immunization for a total of 3 doses.

Cardio-respiratory monitoring and recordings were performed in all patients continuously for 72 hours, beginning 24 hours before and continuing until 48 hours after immunization (Figure 1). Monitoring tracings were printed and CRE were extracted and compared to nurses' surveillance noted in a separate sheet. These analyses were performed by two different operators: a medical fellow (WBJ) and a research nurse. The results were discussed and an agreement reached between operators in any instances of discordance. The recorded CRE included: bradycardia (a 33% decrease in baseline heart rate for at least 4 seconds or a heart rate ≤ 80 bpm), desaturations (10% decrease in baseline saturation), and apnea (respiratory pause of at least 20 seconds, or a respiratory pause of 15 seconds associated with a bradycardia).

Total CRE was expressed as the average number of events (desaturation + apneas + bradycardia) / 24 hours. Δ Total CRE / patient / 24 hours was defined as the difference between the average number of events / 24 hours observed before vs. after immunization for each patient. Biographical data, maternal and pregnancy data, and infant medical data (base line heart rate, temperature and ventilation duration) were also collected for each patient.

Two annotated polysomnographies were performed for all patients with an AURA PSG GRASS ambulatory and wireless system. Each polysomnography had a duration of 2.5 hours: the first was conducted on enrolment (the day before immunization), and the second was conducted 18 to 24 hours after immunization. The patients were settled comfortably in an environment with reduced tactile, auditory and luminous stimulation, and the cardiac electrodes, oximeter and abdominal respiration detector were placed. The polysomnographies were annotated by the research nurse or medical fellow (WBJ) for the total duration of the recordings, and analysis was performed by the team of Pr Pladys (Rennes, France).

CRP and prostaglandin E2 were measured as systemic markers of inflammation. Blood samples for CRP levels were taken at the same time (0.5ml/sample in microtube with lithium heparin and gel barrier), and analyzed by immunoturbidimetric dosage (Sainte-Justine University Hospital Biochemistry laboratory). Capillary blood samples (0.5ml/sample) were collected in an EDTA-coated tube 30-60 min prior to the immunization, and 18h after. 10µM indomethacin was added to each tube within 30 min of sampling in order to inhibit ongoing PG synthesis by platelets. After centrifugation, plasma was frozen (-80ºC) until analysis. Plasma PGE2 concentration was determined by ELISA (PGE2 Parameter Assay kit; R and D systems, #KGE004B; intra- and inter-assay variability of 6.7% and 10.6% respectively).

All blood samples were taken following sucrose administration as per routine practice in the NICU. They also were taken at the same time of a routine blood test already planned for the patients. Δ CRP and Δ PGE2 were defined, respectively, as the difference between CRP and PGE2 levels before and after immunization.

Statistical analysis was performed using SPSS (v20.0 for Windows). All variables were tested for normal distribution using the Shapiro-Wilk normality test. When normally distributed (parametric), data were presented as mean ± standard deviation, applying one-way analysis of variance (ANOVA) and Bonferroni post hoc test. Nonparametric data were analyzed using the Kruskall-Wallis with Dunn post-test. HRV parameters were analyzed by paired or unpaired Student's t-test, or Wilcoxon w-test and Mann-Whitney u-test as appropriate. Correlations between non parametric data were analyzed using Spearmen test. The two-sided significance level was set at 0.05.

The sample size calculation (26 patients required in each group) was based on a 40% incidence of CRE post vaccination \[1,2\] and with the hypothesis that the ibuprofen will decrease this incidence from 40% to 15% (α of 0.05 and a power of 80%).

A post-hoc analysis was performed to identify the pre-immunization characteristics of the preterm infants who increased their CRE of more than 1 SD.

Eligibility criteria: Inclusion Criteria:

* preterm infants less than 32 weeks of gestational age
* Postnatal age more than 7 weeks
* Informed parental consent

Exclusion Criteria:

* anomalies in cardiac conduction
* congenital malformations
* severe intraventricular haemorrhage (grade 3 or 4) or with periventricular leukomalacia

Primary outcomes:
measure: The Change in the Number of CRE (Extracted From Printed Monitoring Tracings Compared to Noted Nurses' Surveillance) Following the First Dose of Pentavalent Vaccine in Preterm Infants Born < 32 Weeks Gestation After Administration of Ibuprofen.
timeFrame: the mean of CRE occured in the 48h after immunization minus the base line CRE : mesured 24h before immunization
Secondary outcomes:
measure: The Modifications in HRV That Can Predict the Occurrence of CRE in Preterm Infants After Immunization.
timeFrame: 72 h
Other outcomes:
Locations:
Study officials:
affiliation: Ste-Justine's hospital
name: Anne Monique Nuyt, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hoch B, Bernhard M. Central apnoea and endogenous prostaglandins in neonates. Acta Paediatr. 2000 Nov;89(11):1364-8. doi: 10.1080/080352500300002589.
citation: Schulzke S, Heininger U, Lucking-Famira M, Fahnenstich H. Apnoea and bradycardia in preterm infants following immunisation with pentavalent or hexavalent vaccines. Eur J Pediatr. 2005 Jul;164(7):432-5. doi: 10.1007/s00431-005-1674-3. Epub 2005 Apr 21.