Frontal Electroencephalography of Neonatal Patients Under Sedation With Opioids and General Anesthesia With Propofol.

Frequently, neonates hospitalized in neonatology units require anesthesia for surgery. The drugs used for this purpose are opioids and other anesthetics, such as propofol.

Currently, the administration of anesthesia is difficult in neonates due to the neurological immaturity of these patients, the scarcity of adequate pharmacological studies, the prolonged use of one or more sedatives prior to surgery and the limited usefulness of current anesthetic monitoring devices in this population.

Electroencephalography (EEG), which has allowed estimation of anesthetic depth in other populations, has been less explored in neonates. To date, there are no EEG markers, correlated with a given dose of anesthesia, that allow an adequate administration in this kind of patients. In this context, a better understanding of the anesthetic effect in the neonatal brain would allow defining characteristic EEG patterns, improving the estimation of anesthetic depth and anesthetic dosage in neonates.

Study Overview

• Status: Completed
• Conditions: Surgery; Anesthesia; Depth of Anesthesia; Neonate
• Intervention / Treatment: Drug: Propofol Group 1; Drug: Propofol Group 2; Drug: Propofol Group 3; Drug: Propofol Group 4

Detailed Description

As a consequence of the cerebral immaturity of newborns (1,2), together with the fact that in the NICU it is common to find patients requiring surgery who are sedated with multiple drugs, it is necessary to define characteristic EEG patterns that allow estimation of the anesthetic depth and adequate dosage of anesthetics, avoiding the the risk of under- or overdosing of anesthetics (3).

The investigators will conduct an exploratory study. The aim of the study is to determine, by frontal electroencephalography, markers of brain electrical activity associated with the administration of propofol in term newborns requiring surgery in the NICU. A sample of 20 term neonatal patients admitted to the NICU UC with a diagnosis of surgical pathology will be included.

General objective:

To describe the characteristics of the frontal electroencephalographic pattern associated with increasing doses of propofol, in term neonates, requiring surgery in the NICU and its correlation with a clinical response, to the surgical stimulus.

Specific objectives:

• Identify the association between electroencephalographic parameters and different levels of sedation prior to surgery.
• To identify the association between electroencephalographic parameters and increasing doses (plasma concentration) of propofol administered in a previously sedated patient.
• To relate the clinical response observed to the surgical stimulus and increasing doses (plasma concentration) of propofol in a previously sedated patient (dose (concentration) - response curve).
• To describe the temporal profile of propofol anesthesia, based on the changes in electroencephalographic parameters observed over time, during the period of administration and suspension of the anesthetic.

On the scheduled day of surgery in the NICU and prior to anesthetic induction, in sedated and standardly monitored patients (ECG, SpO2, PAI, temperature, diuresis). A four-channel SedLine® monitor (Masimo Corporation, Irvine, CA, USA) will be used to monitor frontal brain electrical activity 10 minutes before the induction of anesthesia. At the end of this period, the level of sedation will be evaluated with the N-PASS clinical scale (4) and the types, doses and duration of sedative drugs administered up to that time will be recorded. Then, patients will be randomized into 4 groups, of 5 patients each, to receive manual total intravenous anesthesia, with different propofol infusion rates: Group 1, Propofol 2.0 mg/kg/hr; Group 2, Propofol 4.0 mg/kg/hr; Group 3, Propofol 6.0 mg/kg/hr; Group 4, Propofol 8.0 mg/kg/hrs. At 10 and 20 minutes after the start of the propofol infusion, arterial blood samples will be taken to determine the plasma concentration of propofol reached during the anesthetic induction. In case of hemodynamic alteration (heart rate and/or blood pressure drop by 20%) during the propofol infusion, a 25% decrease of the original dose will be performed. At the end of this period, surgery will be initiated. The hemodynamic and motor response to the surgical stimulus will be observed and recorded. If there is hemodynamic response (increase in heart rate and/or blood pressure by 20%) and/or motor response, after the surgical stimulus, fentanyl rescue 5 mcg/kg/iv will be administered. Subsequent anesthesia will be in the hands of the treating anesthesiologist in the doses and forms he/she deems convenient. Electroencephalographic tracing will be maintained continuously throughout the procedure (from 10 minutes before and up to 10 minutes after surgery). Changes and adjustments to the anesthesia and analgesia given, hemodynamic changes occurring during the procedure and anesthetic and surgical times will be recorded.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Chile
  • Metropolitana
    • Santiago, Metropolitana, Chile, 450881
      • Pontificia Universidad Catolica de Chile

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 1 month (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Term newborns (>37 weeks) admitted to the NICU
• Diagnosis of surgical pathology, non-neurological, to be resolved in the NICU, in the next hours or days.
• Need for continuous sedation-analgesia prior to surgery.

Exclusion criteria:

• Perinatal asphyxia
• Evidence of severe neurological injury.
• Suspected or diagnosed brain malformations
• Uncontrolled metabolic and hemodynamic instability at the time of surgery.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Propofol Group 1; Patients will receive induction of anesthesia with Propofol at a rate of 2.0 mg/kg/hr.	Drug: Propofol Group 1; Propofol 2.0 mg/kg/hr per 10 min; Other Names: Group 1
Experimental: Propofol Group 2; Patients will receive induction of anesthesia with Propofol at a rate of 4.0 mg/kg/hr.	Drug: Propofol Group 2; Propofol 4.0 mg/kg/hr per 10 min; Other Names: Group 2
Experimental: Propofol Group 3; Patients will receive induction of anesthesia with Propofol at a rate of 6.0 mg/kg/hr.	Drug: Propofol Group 3; Propofol 6.0 mg/kg/hr per 10 min; Other Names: Group 3
Experimental: Propofol Group 4; Patients will receive induction of anesthesia with Propofol at a rate of 8.0 mg/kg/hr.	Drug: Propofol Group 4; Propofol 8.0 mg/kg/hr per 10 min; Other Names: Group 4

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electroencephalography monitoring slow bands	Power of frequency slow bands, entropy and complexity measures.	10 minutes before the induction of anesthesia until 10 minutes after emergence of anesthesia, average of 2 hours
Electroencephalography monitoring alpha bands	Power of frequency alpha bands, entropy and complexity measures.	10 minutes before the induction of anesthesia until 10 minutes after emergence of anesthesia, average of 2 hours
Electroencephalography monitoring Theta bands	Power of frequency Theta bands, entropy and complexity measures.	10 minutes before the induction of anesthesia until 10 minutes after emergence of anesthesia, average of 2 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial Pressure	By non invasive Arterial Pressure: Systolic Arterial Pressure in mmHg, diastolic Arterial Pressure in mmHg and Medium Arterial Pressure in mmHg, every 5 minutes.	From induction of anesthesia until surgery starts, average 20 minutes.
Heart Rate	By EKG D-II, every 5 minutes.	From induction of anesthesia until surgery starts, average 20 minutes.
Depth of anesthesia	Evaluated with N-PASS clinical scale. The N-PASS uses five criteria: crying/irritability, behavioral state, facial expression, extremity tone and vital signs. The scale has a range from 0 (normal) to -10 (sedated).	before the induction of anesthesia until the surgery starts, every 10 minutes. An average of 30 minutes.
Propofol plasma concentration	Venous or arterial samples will be taken for propofol plasma concentration levels (ng/ml) at two times (10 minutes and 20 minutes from induction of anesthesia).	from induction of anesthesia up to 20 minutes.
Motor response to surgical incision	Presence of any body movement at the moment of the first surgical incision.	at first surgical incision (average 1 minute).

Collaborators and Investigators

• Sponsor: Pontificia Universidad Catolica de Chile
• Investigators: Principal Investigator: Mauricio C Ibacache, PhD, MD, Associate Professor

Publications and helpful links

General Publications

• Andre M, Lamblin MD, d'Allest AM, Curzi-Dascalova L, Moussalli-Salefranque F, S Nguyen The T, Vecchierini-Blineau MF, Wallois F, Walls-Esquivel E, Plouin P. Electroencephalography in premature and full-term infants. Developmental features and glossary. Neurophysiol Clin. 2010 May;40(2):59-124. doi: 10.1016/j.neucli.2010.02.002. Epub 2010 Mar 16.
• Shany E, Berger I. Neonatal electroencephalography: review of a practical approach. J Child Neurol. 2011 Mar;26(3):341-55. doi: 10.1177/0883073810384866.
• Anand KJ, Willson DF, Berger J, Harrison R, Meert KL, Zimmerman J, Carcillo J, Newth CJ, Prodhan P, Dean JM, Nicholson C; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics. 2010 May;125(5):e1208-25. doi: 10.1542/peds.2009-0489. Epub 2010 Apr 19.
• Giordano V, Edobor J, Deindl P, Wildner B, Goeral K, Steinbauer P, Werther T, Berger A, Olischar M. Pain and Sedation Scales for Neonatal and Pediatric Patients in a Preverbal Stage of Development: A Systematic Review. JAMA Pediatr. 2019 Dec 1;173(12):1186-1197. doi: 10.1001/jamapediatrics.2019.3351.

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2021
• Primary Completion (Actual): December 3, 2022
• Study Completion (Actual): March 3, 2023

Study Registration Dates

• First Submitted: May 12, 2021
• First Submitted That Met QC Criteria: May 23, 2021
• First Posted (Actual): May 27, 2021

Study Record Updates

• Last Update Posted (Actual): March 7, 2023
• Last Update Submitted That Met QC Criteria: March 5, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: surgery; propofol; neonate; Electroencephalography; deph of anesthesia
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Hypnotics and Sedatives; Propofol
• Other Study ID Numbers: 200916011

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes