Endotracheal Intubation, Premedication
Conditions
Keywords
Pain, Newborn, Anaesthesia, opioids, propofol, neuromuscular blocker, atropine
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.
Interventions
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 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
Sponsors
Association Clinique Thérapeutique Infantile du val de Marne
Centre Hospitalier Intercommunal Creteil
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 28 Days
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Intubation Attempts | During intubation procedure, expected duration 1 to 15 minutes | — |
| 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. |
| 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 |
| 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. |
| 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. |
| 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 |
| 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 |
| 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 |
Countries
France
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
Participants by arm
| Arm | Count |
|---|---|
| Atropine Atracurium Sufentanil | 82 |
| Atropine Propofol | 89 |
| Total | 171 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Parents withdrew consent | 0 | 2 |
Baseline characteristics
| Characteristic | Atropine Atracurium Sufentanil | Atropine Propofol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 82 Participants | 89 Participants | 171 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 1 days | 1 days | 1 days |
| Median birth weight [IQR], g | 1130 GRAMS | 1310 GRAMS | 1190 GRAMS |
| Median GA at birth [IQR], weeks | 29 WEEKS | 30 WEEKS | 29 WEEKS |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Reason for intubation, n (%) Apnea | 9 Participants | 3 Participants | 12 Participants |
| Reason for intubation, n (%) Other | 7 Participants | 6 Participants | 13 Participants |
| Reason for intubation, n (%) Respiratory distress syndrome | 50 Participants | 60 Participants | 110 Participants |
| Reason for intubation, n (%) Surgery | 16 Participants | 20 Participants | 36 Participants |
| Region of Enrollment France | 82 participants | 89 participants | 171 participants |
| Sex: Female, Male Female | 25 Participants | 45 Participants | 70 Participants |
| Sex: Female, Male Male | 57 Participants | 44 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 83 | 3 / 80 |
| other Total, other adverse events | 25 / 83 | 28 / 80 |
| serious Total, serious adverse events | 9 / 83 | 16 / 80 |
Outcome results
Primary
Number of Patients With Prolonged Desaturation
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Atropine Atracurium Sufentanil | Number of Patients With Prolonged Desaturation | 54 Participants |
| Atropine Propofol | Number of Patients With Prolonged Desaturation | 53 Participants |
p-value: 0.3895% CI: [-21, 8.1]Mixed Models Analysis
Secondary
Duration of Intubation Procedure
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atropine Atracurium Sufentanil | Duration of Intubation Procedure | 6.0 Minutes |
| Atropine Propofol | Duration of Intubation Procedure | 3.5 Minutes |
Secondary
Heart Rate
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atropine Atracurium Sufentanil | Heart Rate | Heart rate from t-1 to t+9, Difference in bpm | 1.6 bpm | Standard Deviation 25.2 |
| Atropine Atracurium Sufentanil | Heart Rate | Heart rate from t-1 to t+6, Difference in bpm | 3.3 bpm | Standard Deviation 19.5 |
| Atropine Propofol | Heart Rate | Heart rate from t-1 to t+6, Difference in bpm | 11.5 bpm | Standard Deviation 19.6 |
| Atropine Propofol | Heart Rate | Heart rate from t-1 to t+9, Difference in bpm | 11.7 bpm | Standard Deviation 25.3 |
Secondary
Mean Blood Pressure
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
Population: Changes from baseline in mean arterial blood pressure (MAP) were analyzed at predefined time points. Values were missing at some time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atropine Atracurium Sufentanil | Mean Blood Pressure | Mean arterial blood pressure from t-1 to t+30 | -9.1 Difference in mm Hg | Standard Deviation 9.3 |
| Atropine Atracurium Sufentanil | Mean Blood Pressure | Mean arterial blood pressure from t-1 to t+15 | -6.8 Difference in mm Hg | Standard Deviation 12.7 |
| Atropine Propofol | Mean Blood Pressure | Mean arterial blood pressure from t-1 to t+30 | -3.3 Difference in mm Hg | Standard Deviation 9.4 |
| Atropine Propofol | Mean Blood Pressure | Mean arterial blood pressure from t-1 to t+15 | 0.2 Difference in mm Hg | Standard Deviation 12.7 |
Secondary
Number of Intubation Attempts
Time frame: During intubation procedure, expected duration 1 to 15 minutes
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Atropine Atracurium Sufentanil | Number of Intubation Attempts | 1 attempt | 41 Participants |
| Atropine Atracurium Sufentanil | Number of Intubation Attempts | 2 attempts | 25 Participants |
| Atropine Atracurium Sufentanil | Number of Intubation Attempts | > 2 attempts | 21 Participants |
| Atropine Atracurium Sufentanil | Number of Intubation Attempts | Missing data | 2 Participants |
| Atropine Propofol | Number of Intubation Attempts | Missing data | 1 Participants |
| Atropine Propofol | Number of Intubation Attempts | 1 attempt | 47 Participants |
| Atropine Propofol | Number of Intubation Attempts | > 2 attempts | 11 Participants |
| Atropine Propofol | Number of Intubation Attempts | 2 attempts | 23 Participants |
Secondary
Number of Patients Surviving Without Ages and Stages Questionnaire Score Below Threshold at Age 2
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Atropine Atracurium Sufentanil | Number of Patients Surviving Without Ages and Stages Questionnaire Score Below Threshold at Age 2 | 38 Participants |
| Atropine Propofol | Number of Patients Surviving Without Ages and Stages Questionnaire Score Below Threshold at Age 2 | 45 Participants |
Secondary
Pulse Oxymetry
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
Population: Changes in SpO2 value from baseline were analyzed at predefined time points. Data was missing at some time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atropine Atracurium Sufentanil | Pulse Oxymetry | SpO2 from t-1 to t+6, Difference in % | -6.0 % SpO2 | Standard Deviation 20.1 |
| Atropine Atracurium Sufentanil | Pulse Oxymetry | SpO2 from t-1 to t+9, Difference in % | -8.7 % SpO2 | Standard Deviation 22.3 |
| Atropine Propofol | Pulse Oxymetry | SpO2 from t-1 to t+9, Difference in % | -15.9 % SpO2 | Standard Deviation 22.2 |
| Atropine Propofol | Pulse Oxymetry | SpO2 from t-1 to t+6, Difference in % | -12.0 % SpO2 | Standard Deviation 20.1 |
Secondary
Short Term Neurological Outcome: Worsening of Head Ultrasound
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Atropine Atracurium Sufentanil | Short Term Neurological Outcome: Worsening of Head Ultrasound | 14 Participants |
| Atropine Propofol | Short Term Neurological Outcome: Worsening of Head Ultrasound | 12 Participants |
Secondary
Transcutaneous PCO2 (TcPCO2) Measurement
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
Population: Changes in TcPCO2 from baseline were analyzed at predefined time points. Values were missing at some time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atropine Atracurium Sufentanil | Transcutaneous PCO2 (TcPCO2) Measurement | TcPCO2 from t-1 to t+15 | 8.0 Difference in mm Hg | Standard Deviation 14.4 |
| Atropine Atracurium Sufentanil | Transcutaneous PCO2 (TcPCO2) Measurement | TcPCO2 from t-1 to t+30 | 5.1 Difference in mm Hg | Standard Deviation 19.1 |
| Atropine Propofol | Transcutaneous PCO2 (TcPCO2) Measurement | TcPCO2 from t-1 to t+15 | 14.1 Difference in mm Hg | Standard Deviation 14.4 |
| Atropine Propofol | Transcutaneous PCO2 (TcPCO2) Measurement | TcPCO2 from t-1 to t+30 | 16.2 Difference in mm Hg | Standard Deviation 19.3 |