PRETTINEO: Premedication Trial for Tracheal Intubation of the NEOnate

• Sponsor: Centre Hospitalier Intercommunal Creteil (Other)
• Overall Status: Completed
• CT.gov ID: NCT01490580
• Collaborator: Association Clinique Thérapeutique Infantile du val de Marne (Other)
• Enrollment: 173
• Locations: 6
• Arms: 2
• Actual Duration (Months): 95.5
• Patients Per Site: 28.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Multicenter double blind randomized controlled trial comparing "atropine+propofol" vs "atropine+atracurium+sufentanil" as a premedication prior to endotracheal intubation of the neonate.

Primary outcome: pulse oxymetry value < 80% for more than 60 seconds. Secondary outcomes:

number of attempts, duration of the procedure, changes in physiologic parameters, short- and long-term neurodevelopmental outcome.

Hypothesis: "atropine + propofol" compared to "atropine+atracurium+sufentanil" will significantly reduce the frequency of severe hypoxemia.

Condition or Disease	Intervention/Treatment	Phase
Premedication; Endotracheal Intubation	Drug: atropine+ propofol; Drug: atropine + atracurium + sufentanil	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 173 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Double Blind Randomized Controlled Trial Comparing "Atropine+Propofol" Versus "Atropine+Atracurium+Sufentanil" as a Premedication Prior to Semi-urgent or Elective Endotracheal Intubation of Term and Preterm Newborns
• Actual Study Start Date: May 1, 2012
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Apr 15, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Atropine + Propofol	Drug: atropine+ propofol; Atropine bolus: 20 µg/kg Propofol injected over 60 seconds: 1 mg/kg for infants < 1000g - Renewable once 2.5 mg/kg for infants > 1000G - Possible additional dose of 1 mg/kg
Active Comparator: Atropine + atracurium + sufentanil	Drug: atropine + atracurium + sufentanil; Atropine bolus: 20 µg/kg Atracurium: 0.3 mg/kg- Possible additional dose of 0.1 mg/kg Sufentanil: 0.1 µg/kg for infants < 1000g 0.2 µg/kg for infants > 1000g

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Prolonged Desaturation [During intubation procedure, expected duration 1 to 15 minutes]

   Pulse oxymetry value measured by Masimo technology below 80% for 60 seconds or more. Duration of intubation is defined by the time between first laryngoscope insertion and last laryngoscope removal after successful intubation. Successful intubation is defined by clear bilateral breath sounds, increasing heart rate and saturation (if previously low) and appropriate flow curves on the ventilator.

Secondary Outcome Measures

1. Number of Intubation Attempts [During intubation procedure, expected duration 1 to 15 minutes]

2. Duration of Intubation Procedure [Expected duration 1 to 15 minutes]

   Although the initial definition of procedure duration in the registered protocol was the time between the first laryngoscope insertion and last laryngoscope removal after successful intubation, the variable collected in the clinical research form was defined as the time between first laryngoscope insertion and the fixation of the tube with tape.

3. Heart Rate [from 1 minute before to 60 minutes after the start of premedication]

   Heart rate recordings 1 minute before the first injection and at 3, 6, 9, 12, 15, 30, 45 and 60 minutes after the first injection

4. Short Term Neurological Outcome: Worsening of Head Ultrasound [Within 7 days after inclusion]

   Worsening of head ultrasound scans in the 7 days after intubation from the preinclusion evaluation, defined as either a normal scan before inclusion and any grade intraventricular hemorrhage (IVH) afterwards, or as a preinclusion grade 1 or 2 IVH scan deteriorating to grade 3 or 4 IVH, according to Papile's classification; This analysis was not centralized but performed in each center according to its usual protocols.

5. Number of Patients Surviving Without Ages and Stages Questionnaire Score Below Threshold at Age 2 [At 2 years corrected age]

   Survival without risk of neurodevelopmental delay. Risk of neurodevelopmental delay was defined as no Ages and Stages Questionnaires (ASQ) domain score below threshold (-2 SD) at 2 years of corrected age. The ASQ includes 30 items in 5 neurodevelopmental domains: communication abilities, gross motor skills, fine motor skills, problem solving abilities, and personal-social skills. For each domain, the score obtained by the sum of the items ranges from 0 to 60 and the overall maximum ASQ score is 300 points. For each domain, the score can be categorized using established screening thresholds: an ASQ score <-2 SD below the mean suggests a risk of neurodevelopmental delay in that domai.

6. Pulse Oxymetry [from 1 minute before to 60 minutes after the start of premedication]

   Pulse oxymetry recordings 1 minute before the first injection and at 3, 6, 9, 12, 15, 30, 45 and 60 minutes after the first injection

7. Mean Blood Pressure [from 1 minute before to 60 minutes after the start of premedication]

   Blood pressure recordings 1 minute before the first injection and at 3, 6, 9, 12, 15, 30, 45 and 60 minutes after the first injection

8. Transcutaneous PCO2 (TcPCO2) Measurement [from 1 minute before to 60 minutes after the start of premedication]

   TcPCO2 recordings 1 minute before the first injection and at 3, 6, 9, 12, 15, 30, 45 and 60 minutes after the first injection

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 28 Days
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Corrected age < 45 weeks of gestational age

• Currently hospitalized in a neonatal intensive care unit

• Requiring semi-urgent or elective intubation

• Equipped with a reliable and permeable IV line

• Parental consent

Exclusion Criteria:

• Lack of parental consent

• Parental refusal

• Sedative or anesthetic treatment in the previous 24 hours

• Hemodynamic compromise defined as mean blood pressure< corrected GA and/or refill time

3 seconds

• Upper airway malformation

• Life-threatening situation requiring immediate intubation

• Inclusion in another trial not permitting any other participation

• Impossibility to establish venous access

• Any contra-indication to any experimental drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Médecine Néonatale et Réanimation Pédiatrique Polyvalente, CHU Amiens Nord	Amiens		France	80054
2	Hôpital Mère-Enfant	Bron		France	69677
3	CHU de Caen	Caen		France
4	Centre Hospitalier Intercommunal de Créteil	Créteil		France	94000
5	Hôpital des Enfants	Toulouse		France	31059
6	Réanimation Pédiatrique et Néonatale de l'hôpital Clochevile, Centre Hospitalier Universitaire de Tours	Tours		France	37044

Sponsors and Collaborators

• Centre Hospitalier Intercommunal Creteil
• Association Clinique Thérapeutique Infantile du val de Marne

Investigators

• Principal Investigator: Xavier Durrmeyer, MD, CHI Creteil

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 1, 2018

More Information

Publications

None provided.

• Responsible Party: Xavier Durrmeyer, Principal Investigator, Centre Hospitalier Intercommunal Creteil
• ClinicalTrials.gov Identifier: NCT01490580
• Other Study ID Numbers: PRETTINEO
• First Posted: Dec 13, 2011
• Last Update Posted: Mar 4, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Xavier Durrmeyer, Principal Investigator, Centre Hospitalier Intercommunal Creteil: Pain; Newborn; Anaesthesia; opioids; propofol; neuromuscular blocker; atropine
• Additional relevant MeSH terms: Atropine; Sufentanil; Propofol; Atracurium

Study Results

Participant Flow

Recruitment Details	The trial was prematurely interrupted for logistic reasons in July 2016: a fourth drug manufacturing run was necessary because the intralipids had passed their expiration date and funding had run out. During the study period, 755 patients were screened for eligibility, and 173 randomized

Arm/Group Title	Atropine Atracurium Sufentanil	Atropine Propofol
Arm/Group Description	n=82 allocated to atropine+atracurium+sufentanil n=80 received allocated intervention n=2 did not receive allocated intervention n=1 never intubated n=1 received another premedication 82 included in final analysis	n=91 allocated to atropine+propofol n= 2 excluded for lack of consent n=83 received allocated intervention n=6 did not receive allocated intervention n=2 never intubated n=4 received another premedication 89 included in final analysis
Period Title: Overall Study
STARTED	82	91
COMPLETED	82	89
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Atropine Atracurium Sufentanil	Atropine Propofol	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	82	89	171
Age (Count of Participants)
<=18 years	82 100%	89 100%	171 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (days) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [days]	1	1	1
Sex: Female, Male (Count of Participants)
Female	25 30.5%	45 50.6%	70 40.9%
Male	57 69.5%	44 49.4%	101 59.1%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
France	82 100%	89 100%	171 100%
Median GA at birth [IQR], weeks (WEEKS) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [WEEKS]	29	30	29
Median birth weight [IQR], g (GRAMS) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [GRAMS]	1130	1310	1190
Reason for intubation, n (%) (Count of Participants)
Respiratory distress syndrome	50 61%	60 67.4%	110 64.3%
Apnea	9 11%	3 3.4%	12 7%
Surgery	16 19.5%	20 22.5%	36 21.1%
Other	7 8.5%	6 6.7%	13 7.6%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Prolonged Desaturation
Description	Pulse oxymetry value measured by Masimo technology below 80% for 60 seconds or more. Duration of intubation is defined by the time between first laryngoscope insertion and last laryngoscope removal after successful intubation. Successful intubation is defined by clear bilateral breath sounds, increasing heart rate and saturation (if previously low) and appropriate flow curves on the ventilator.
Time Frame	During intubation procedure, expected duration 1 to 15 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atropine Atracurium Sufentanil	Atropine Propofol
Arm/Group Description
Measure Participants	82	89
Count of Participants [Participants]	54 65.9%	53 59.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atropine Atracurium Sufentanil, Atropine Propofol
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.38
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-6.4
	Confidence Interval	(2-Sided) 95%; -21.0 to 8.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Intubation Attempts
Time Frame	During intubation procedure, expected duration 1 to 15 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atropine + Propofol	Atropine + Atracurium + Sufentanil
Arm/Group Description	atropine+ propofol: Atropine bolus: 20 µg/kg Propofol injected over 60 seconds: 1 mg/kg for infants < 1000g - Renewable once 2.5 mg/kg for infants > 1000G - Possible additional dose of 1 mg/kg	atropine + atracurium + sufentanil: Atropine bolus: 20 µg/kg Atracurium: 0.3 mg/kg- Possible additional dose of 0.1 mg/kg Sufentanil: 0.1 µg/kg for infants < 1000g 0.2 µg/kg for infants > 1000g
Measure Participants	89	82
1 attempt	41 50%	47 52.8%
2 attempts	25 30.5%	23 25.8%
> 2 attempts	21 25.6%	11 12.4%
Missing data	2 2.4%	1 1.1%

3. Secondary Outcome

Title	Duration of Intubation Procedure
Description	Although the initial definition of procedure duration in the registered protocol was the time between the first laryngoscope insertion and last laryngoscope removal after successful intubation, the variable collected in the clinical research form was defined as the time between first laryngoscope insertion and the fixation of the tube with tape.
Time Frame	Expected duration 1 to 15 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atropine + Propofol	Atropine + Atracurium + Sufentanil
Arm/Group Description	atropine+ propofol: Atropine bolus: 20 µg/kg Propofol injected over 60 seconds: 1 mg/kg for infants < 1000g - Renewable once 2.5 mg/kg for infants > 1000G - Possible additional dose of 1 mg/kg	atropine + atracurium + sufentanil: Atropine bolus: 20 µg/kg Atracurium: 0.3 mg/kg- Possible additional dose of 0.1 mg/kg Sufentanil: 0.1 µg/kg for infants < 1000g 0.2 µg/kg for infants > 1000g
Measure Participants	84	80
Median (Inter-Quartile Range) [Minutes]	6.0	3.5

4. Secondary Outcome

Title	Heart Rate
Description	Heart rate recordings 1 minute before the first injection and at 3, 6, 9, 12, 15, 30, 45 and 60 minutes after the first injection
Time Frame	from 1 minute before to 60 minutes after the start of premedication

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atropine + Propofol	Atropine + Atracurium + Sufentanil
Arm/Group Description	atropine+ propofol: Atropine bolus: 20 µg/kg Propofol injected over 60 seconds: 1 mg/kg for infants < 1000g - Renewable once 2.5 mg/kg for infants > 1000G - Possible additional dose of 1 mg/kg	atropine + atracurium + sufentanil: Atropine bolus: 20 µg/kg Atracurium: 0.3 mg/kg- Possible additional dose of 0.1 mg/kg Sufentanil: 0.1 µg/kg for infants < 1000g 0.2 µg/kg for infants > 1000g
Measure Participants	86	80
Heart rate from t-1 to t+6, Difference in bpm	3.3 (19.5)	11.5 (19.6)
Heart rate from t-1 to t+9, Difference in bpm	1.6 (25.2)	11.7 (25.3)

5. Secondary Outcome

Title	Short Term Neurological Outcome: Worsening of Head Ultrasound
Description	Worsening of head ultrasound scans in the 7 days after intubation from the preinclusion evaluation, defined as either a normal scan before inclusion and any grade intraventricular hemorrhage (IVH) afterwards, or as a preinclusion grade 1 or 2 IVH scan deteriorating to grade 3 or 4 IVH, according to Papile's classification; This analysis was not centralized but performed in each center according to its usual protocols.
Time Frame	Within 7 days after inclusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atropine + Propofol	Atropine + Atracurium + Sufentanil
Arm/Group Description	atropine+ propofol: Atropine bolus: 20 µg/kg Propofol injected over 60 seconds: 1 mg/kg for infants < 1000g - Renewable once 2.5 mg/kg for infants > 1000G - Possible additional dose of 1 mg/kg	atropine + atracurium + sufentanil: Atropine bolus: 20 µg/kg Atracurium: 0.3 mg/kg- Possible additional dose of 0.1 mg/kg Sufentanil: 0.1 µg/kg for infants < 1000g 0.2 µg/kg for infants > 1000g
Measure Participants	68	68
Count of Participants [Participants]	14 17.1%	12 13.5%

6. Secondary Outcome

Title	Number of Patients Surviving Without Ages and Stages Questionnaire Score Below Threshold at Age 2
Description	Survival without risk of neurodevelopmental delay. Risk of neurodevelopmental delay was defined as no Ages and Stages Questionnaires (ASQ) domain score below threshold (-2 SD) at 2 years of corrected age. The ASQ includes 30 items in 5 neurodevelopmental domains: communication abilities, gross motor skills, fine motor skills, problem solving abilities, and personal-social skills. For each domain, the score obtained by the sum of the items ranges from 0 to 60 and the overall maximum ASQ score is 300 points. For each domain, the score can be categorized using established screening thresholds: an ASQ score <-2 SD below the mean suggests a risk of neurodevelopmental delay in that domai.
Time Frame	At 2 years corrected age

Outcome Measure Data

Analysis Population Description

To handle missing data on ASQ scores, we performed multiple imputation with chained equations using the SAS "MI" procedure. The primary analysis was performed on the imputed dataset in the "as treated" study groups.

Arm/Group Title	Atropine Atracurium Sufentanil "as Treated" Population	Atropine Propofol "as Treated" Population
Arm/Group Description	n=81 n=79 Received intervention as randomized n=2 Allocated to atropine + propofol but did not receive propofol and received atracurium + sufentanil as open-label drug	n=85 n=83 Received intervention as randomized n=1 Allocated to atropine + atracurium + sufentanil but received propofol as open-label drug n=1 Allocated to atropine + propofol but did not receive intervention as randomized, received open-label atropine + propofol
Measure Participants	81	85
Count of Participants [Participants]	38 46.3%	45 50.6%

7. Secondary Outcome

Title	Pulse Oxymetry
Description	Pulse oxymetry recordings 1 minute before the first injection and at 3, 6, 9, 12, 15, 30, 45 and 60 minutes after the first injection
Time Frame	from 1 minute before to 60 minutes after the start of premedication

Outcome Measure Data

Analysis Population Description

Changes in SpO2 value from baseline were analyzed at predefined time points. Data was missing at some time points.

Arm/Group Title	Atropine + Propofol	Atropine + Atracurium + Sufentanil
Arm/Group Description	atropine+ propofol: Atropine bolus: 20 µg/kg Propofol injected over 60 seconds: 1 mg/kg for infants < 1000g - Renewable once 2.5 mg/kg for infants > 1000G - Possible additional dose of 1 mg/kg	atropine + atracurium + sufentanil: Atropine bolus: 20 µg/kg Atracurium: 0.3 mg/kg- Possible additional dose of 0.1 mg/kg Sufentanil: 0.1 µg/kg for infants < 1000g 0.2 µg/kg for infants > 1000g
Measure Participants	85	80
SpO2 from t-1 to t+6, Difference in %	-6.0 (20.1)	-12.0 (20.1)
SpO2 from t-1 to t+9, Difference in %	-8.7 (22.3)	-15.9 (22.2)

8. Secondary Outcome

Title	Mean Blood Pressure
Description	Blood pressure recordings 1 minute before the first injection and at 3, 6, 9, 12, 15, 30, 45 and 60 minutes after the first injection
Time Frame	from 1 minute before to 60 minutes after the start of premedication

Outcome Measure Data

Analysis Population Description

Changes from baseline in mean arterial blood pressure (MAP) were analyzed at predefined time points. Values were missing at some time points.

Arm/Group Title	Atropine + Propofol	Atropine + Atracurium + Sufentanil
Arm/Group Description	atropine+ propofol: Atropine bolus: 20 µg/kg Propofol injected over 60 seconds: 1 mg/kg for infants < 1000g - Renewable once 2.5 mg/kg for infants > 1000G - Possible additional dose of 1 mg/kg	atropine + atracurium + sufentanil: Atropine bolus: 20 µg/kg Atracurium: 0.3 mg/kg- Possible additional dose of 0.1 mg/kg Sufentanil: 0.1 µg/kg for infants < 1000g 0.2 µg/kg for infants > 1000g
Measure Participants	80	77
Mean arterial blood pressure from t-1 to t+15	-6.8 (12.7)	0.2 (12.7)
Mean arterial blood pressure from t-1 to t+30	-9.1 (9.3)	-3.3 (9.4)

9. Secondary Outcome

Title	Transcutaneous PCO2 (TcPCO2) Measurement
Description	TcPCO2 recordings 1 minute before the first injection and at 3, 6, 9, 12, 15, 30, 45 and 60 minutes after the first injection
Time Frame	from 1 minute before to 60 minutes after the start of premedication

Outcome Measure Data

Analysis Population Description

Changes in TcPCO2 from baseline were analyzed at predefined time points. Values were missing at some time points.

Arm/Group Title	Atropine + Propofol	Atropine + Atracurium + Sufentanil
Arm/Group Description	atropine+ propofol: Atropine bolus: 20 µg/kg Propofol injected over 60 seconds: 1 mg/kg for infants < 1000g - Renewable once 2.5 mg/kg for infants > 1000G - Possible additional dose of 1 mg/kg	atropine + atracurium + sufentanil: Atropine bolus: 20 µg/kg Atracurium: 0.3 mg/kg- Possible additional dose of 0.1 mg/kg Sufentanil: 0.1 µg/kg for infants < 1000g 0.2 µg/kg for infants > 1000g
Measure Participants	32	29
TcPCO2 from t-1 to t+15	8.0 (14.4)	14.1 (14.4)
TcPCO2 from t-1 to t+30	5.1 (19.1)	16.2 (19.3)

Adverse Events

Arm/Group Title	Atropine + Propofol		Atropine + Atracurium + Sufentanil
Arm/Group Description	atropine+ propofol: Atropine bolus: 20 µg/kg Propofol injected over 60 seconds: 1 mg/kg for infants < 1000g - Renewable once 2.5 mg/kg for infants > 1000G - Possible additional dose of 1 mg/kg		atropine + atracurium + sufentanil: Atropine bolus: 20 µg/kg Atracurium: 0.3 mg/kg- Possible additional dose of 0.1 mg/kg Sufentanil: 0.1 µg/kg for infants < 1000g 0.2 µg/kg for infants > 1000g
All Cause Mortality
	Atropine + Propofol		Atropine + Atracurium + Sufentanil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/83 (2.4%)		3/80 (3.8%)
Serious Adverse Events
	Atropine + Propofol		Atropine + Atracurium + Sufentanil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/83 (10.8%)		16/80 (20%)
Cardiac disorders
Cardiac arrest	1/83 (1.2%)	1	1/80 (1.3%)	1
General disorders
OTHER	1/83 (1.2%)	1	1/80 (1.3%)	1
Respiratory, thoracic and mediastinal disorders
Death	2/83 (2.4%)	2	3/80 (3.8%)	3
Thoracic rigidity	3/83 (3.6%)	3	11/80 (13.8%)	11
Vascular disorders
Hypotension (treated)	2/83 (2.4%)	2	0/80 (0%)	0
Other (Not Including Serious) Adverse Events
	Atropine + Propofol		Atropine + Atracurium + Sufentanil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/83 (30.1%)		28/80 (35%)
Cardiac disorders
Bradycardia	1/83 (1.2%)	1	6/80 (7.5%)	6
General disorders
Other	12/83 (14.5%)	12	14/80 (17.5%)	14
Vascular disorders
Hypotension, not treated	9/83 (10.8%)	9	1/80 (1.3%)	1
Hypertension	7/83 (8.4%)	7	7/80 (8.8%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.