Lorazepam for the Analgosedation of Pediatric Patients in Mechanical Ventilation.

Bambino Gesù Hospital and Research Institute

Status and phase: Unknown; Phase 2

Conditions: Analgesia

Treatments: Drug: Lorazepam 4 mg/ml

Study type: Interventional

Funder types: Other

Identifiers

NCT04646135

2019-003901-93 (EudraCT Number)

1954 / 2019

Details and patient eligibility

About

The aim of this study is to better define the pharmacokinetic and pharmacodynamic profile of lorazepam for the analgosedation in pediatric intensive care unit. This will help to better define the dosages and administration modalities (bolus or continue infusion) required to achieve analgosedation with lorazepam in pediatric patients undergoing mechanical ventilation.

Full description

The prolonged use of certain sedative drugs such as midazolam, whose metabolism is associated with the production of active metabolites, can lead to difficult management of sedative therapy and ventilatory weaning. The active metabolites, whose production is variable, determine in fact a difficulty in establishing a precision therapy, thus making it necessary to identify new molecules for sedation in pediatric intensive care unit (PICU). Lorazepam (LZ) is a benzodiazepine with an intermediate duration of activity, administered by continuous infusion or intermittent bolus, which has the advantages of higher potency compared to other benzodiazepines, a low cost and a metabolism that does not produce active metabolites. However, the presence of propylene glycol (PG), an excipient present in intravenous LZ formulations, although generally well tolerated, is potentially associated with episodes of tissue toxicity due to accumulation phenomena; this may represent a risk in cases where LZ is administered in high doses. This study, based on pharmacokinetic models obtained from data already available in the scientific literature, aims to define the pharmacokinetic and pharmacodynamic characteristics of LZ for the analgosedation of pediatric patients admitted to intensive care and subjected to mechanical ventilation. Preliminary evaluation of sedative efficacy will be carried out through COMFORT-B scale assessment.

Enrollment: 9 estimated patients

Sex: All

Ages: 1 to 11 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Informed written consent of the parents or legal representatives of minors according to national law;
• Male and/or female subjects of the following ages: ≥1 year - <12 years;
• Critical patients who need to undergo mechanical ventilation and hospitalized in PICU;

Exclusion criteria

• Hospitalization in PICU expected to be less than 48 hours long;
• Altered renal function (eGFR according to Schwartz < 30 mL/min/1.73 m2 or creatininemia > 2 vn);
• Altered liver function (bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 2 NU);
• Altered cardiac function (Ejection Fraction < 50%);
• Need for administration of neuromuscular blocking drugs;
• Concomitant therapy with continuous infusion drugs containing PG;
• Metronidazole therapy in the three months prior to enrollment;
• History of exposure to LZ in the seven days prior to enrollment;
• Participation in other experimental clinical trials;
• Patient undergoing extracorporeal circulation (dialysis, ECMO)
• Known allergic reaction to LZ or its excipients;
• Weight < 9 kg;
• Known immaturity of the enzymatic system of alcohol dehydrogenase;
• Pregnancy in progress;
• Ingestion of antifreeze;
• Treatment with silver sulfadiazine for wound care;
• Oncological pathology diagnosed or suspected;
• Valproic acid therapy
• Patients undergoing continuous infusion therapy with drugs used for sedation prior to admission to the red area (excluding dexmedetomidine).

Trial design

Primary purpose: Supportive Care

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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9 participants in 3 patient groups

Sequence 1

Experimental group

Description:

The subjects enrolled in this arm, will undergo the following lorazepam administration scheme: * Day 1: 6 Boluses at 0.1 mg/kg LZ every 4 hours * Day 2: 6 Boluses at 0.2 mg/kg LZ every 4 hours * Day 3: Continuous Infusion at 0.025 mg/kg/hour LZ

Treatment:

Drug: Lorazepam 4 mg/ml

Sequence 2

Experimental group

Description:

The subjects enrolled in this arm, will undergo the following lorazepam administration scheme: * Day 1: 6 Boluses at 0.2 mg/kg LZ every 4 hours * Day 2: 6 Boluses at 0.1 mg/kg LZ every 4 hours * Day 3: Continuous Infusion at 0.03 mg/kg/hour LZ

Treatment:

Drug: Lorazepam 4 mg/ml

Sequence 3

Experimental group

Description:

The subjects enrolled in this arm, will undergo the following lorazepam administration scheme: * Day 1: 6 Boluses at 0.3 mg/kg LZ every 4 hours * Day 2: 6 Boluses at 0.1 mg/kg LZ every 4 hours * Day 3: Continuous Infusion at 0.025 mg/kg/hour LZ

Treatment:

Drug: Lorazepam 4 mg/ml