Determination of the Optimal Dose of Ephedrine in Intraoperative Arterial Hypotension of Newborns and Infants up to 6 Months of Age.

Study Overview
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Brief Summary
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The incidence of arterial hypotension under general anesthesia using sevoflurane is particularly high in newborns and infants up to 6 months of age. A decrease of 20% of the initial mean blood pressure (mBP) is the definition of significant arterial hypotension in adults and children. In adults, intraoperative arterial hypotension is associated with an increase of intraoperative mortality and a certain neurological morbidity. In infants under 6 months of age, neurological disorders have been reported following general anesthesia. Neurotoxicity of hypnotics is often incriminated as should be the episodes of arterial hypotension. Current management of hypotension uses vascular filling with crystalloids and vasopressive amines in second intention. Dopamine is the most frequently used amine. Ephedrine can also be used. Ephedrine is particularly interesting because of its action on both α and β receptors and its mode of administration: one dose and peripheral access. Only one study is available in children from birth to adulthood; it demonstrates a lower hemodynamic response in infants than in adults, when administered a low dose of Ephedrine (0.1 to 0.2 mg/kg). A recent retrospective cohort suggests an under efficacy of low doses and the use of higher doses than those recommended. The primary objective is to determine the optimal dose of ephedrine (dose of ephedrine associated with a difference of proportion of newborns/infants in therapeutic success of 55%) compare to the reference dose of 0.1mg/kg as a first line treatment of intraoperative arterial hypotension. Secondary objectives: Return to a mBP superior to 38mmHg post Ephedrine administration. To assess occurrence of hypoxemic events during anesthesia. To assess tolerance of ephedrine. One hundred and twenty newborn and infants up to 6 months of age will be recruited in 3 sites of the Rhone Alpes Auvergne area over 24 months.

Official Title
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Determination of the Optimal Dose of Ephedrine in Intraoperative Arterial Hypotension of Newborns and Infants up to 6 Months of Age. A Randomized, Controlled, Open-label, Dose Escalation Study.

Conditions
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Intraoperative Arterial Hypotension, Infant, Newborn

Intervention / Treatment
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* Drug: Ephedrine 30mg/10mL injectable solution, single administration, dose : 0.6, 0.8, 1.0, 1.2 and 1.4 mg/kG
* Drug: Ephedrine 30mg/10mL injectable solution, single administration, dose : 0.1 mg/kG.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newborns or infants < 6 months of age, boys and girls, premature or not, requiring general anesthesia induced by sevoflurane who presents during anesthesia a decrease of blood pressure superior to 20% of the basal mBP (measured prior to surgery) despite of vascular filling with sodium chloride 0.9% (10mL/kg during 10 min). Written, informed consent obtained from the 2 parents Exclusion Criteria: Allergy to Ephedrine. Emergency surgery. Patient having previously received other vasopressive amines. Use of other indirect sympathomimetic drug such as phenylpropanolamine, phenylephrine, pseudoephedrine and methylphenidate. Premedication with clonidine Congenital heart disease IV-induced anesthesia.

Ages Eligible for Study
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Maximum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ephedrine, dose : 0.6, 0.8, 1.0, 1.2 and 1.4 mg/kG<br>Dose escalation: 6 successive cohorts with a maximal increasing dose | Drug: Ephedrine 30mg/10mL injectable solution, single administration, dose : 0.6, 0.8, 1.0, 1.2 and 1.4 mg/kG<br> <br> |
| Active Comparator: Ephedrine, dose : 0.1 mg/kG, reference dose<br>Reference dose | Drug: Ephedrine 30mg/10mL injectable solution, single administration, dose : 0.1 mg/kG.<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Therapeutic success is defined as a mBP superior to 55% of the basal mBP (prior to anesthesia) within 10 minutes post Ephedrine administration |  | Continuous monitoring within 10 minutes post-administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Return to a mBP superior to 38mmHg within 10 minutes post Ephedrine administration |  | Continuous monitoring within 10 minutes post-administration | 
| Variations of O2 saturation in cerebral tissue (number of desaturations, evolution under treatment) using a Near Infrared Spectroscopy (NIRS) technology |  | Continuous monitoring within 10 minutes post-administration | 
| Tolerance of Ephedrine: occurrence of serious adverse events | Clinical examination focusing specifically on heart rate and hypertension | During 3 days post-administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric, intraoperative arterial hypotension, ephedrine, general anesthesia