Lorazepam for the Analgosedation of Pediatric Patients in Mechanical Ventilation.

Not for Profit, Monocentric, Open Label Trial of Lorazepam, Randomized to Three Different Sequences of Boli and Continuous Infusion, for Sedation of Children Aged ≥1 and <12 Years Admitted in Intensive Care and Mechanically Ventilated.

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.

Study Overview

• Status: Unknown
• Conditions: Analgesia
• Intervention / Treatment: Drug: Lorazepam 4 mg/ml

Detailed 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.

• Study Type: Interventional
• Enrollment (Anticipated): 9
• Phase: Phase 2

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 11 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence 1; 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	Drug: Lorazepam 4 mg/ml; Lorazepam will be administered intravenously according to the scheduled sequences.
Experimental: Sequence 2; 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	Drug: Lorazepam 4 mg/ml; Lorazepam will be administered intravenously according to the scheduled sequences.
Experimental: Sequence 3; 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	Drug: Lorazepam 4 mg/ml; Lorazepam will be administered intravenously according to the scheduled sequences.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lorazepam Pharmacokinetics (AUC)	AUC of Lorazepam	72 hours from enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analgosedative efficacy of Lorazepam	Frequency of responder patients (COMFORT-B scale score between 11 and 22 and alertness score between 2 and 3)	72 hours from enrollment
COMFORT-BEHAVIOURAL (COMFORT-B) scale	Median (IQR) of COMFORT-B scale score and alertness score. The COMFORT BEHAVIOURAL (COMFORT-B) SCALE consists of six items: alertness, calmness, respiratory response (for children undergoing mechanical ventilation), body movements, facial tension and muscle tone. Each item goes from 1 to 5, assessing the different intensities. The sum of the six ratings leads to a final score ranging from a minimum of 6 to a maximum of 30. A patient is considered to be under-sedated in case of COMFORT-B scores of 23 or higher, over-sedated in case of COMFORT-B scores of 10 or lower.	72 hours from enrollment
Dropouts due to any adverse event	Number of interruptions of the experimental administration sequence due to adverse events	72 hours from enrollment
Adverse Events (AEs)/ Serious Adverse Events (SAEs) registration at end of study	Number of AEs / SAEs at the end of the administration of the experimental drug	72 hours from enrollment
AEs/SAEs registration at end of follow-up	Number of AEs / SAEs at the end of the follow-up period	6 days from enrollment
Vital signs at the end of study (Blood Pressure)	Blood Pressure measurement in mmHg, change from baseline (Median (IQR))	72 hours from enrollment
Vital signs at the end of study (Heart Rate)	Heart rate measurement in beats per minute (b.p.m), change from baseline (Median (IQR))	72 hours from enrollment
Vital signs at the end of study (Body Temperature)	Body temperature measurement in °C, change from baseline (Median (IQR))	72 hours from enrollment
Vital signs at the end of follow-up (Blood Pressure)	Blood Pressure measurement in mmHg, change from baseline (Median (IQR))	6 days from enrollment
Vital signs at the end of follow-up (Heart Rate)	Heart rate measurement in beats per minute (b.p.m), change from baseline (Median (IQR))	6 days from enrollment
Vital signs at the end of follow-up (Body Temperature)	Body temperature measurement in °C, change from baseline (Median (IQR))	6 days from enrollment
Plasma concentrations of Propylene Glycol at the end of study	AUC of PG in mg/L in serum	72 hours from enrollment
Osmol gap at the end of study	Osmol gap (detected osmolarity - calculated osmolarity) change from baseline (Median (IQR)	72 hours from enrollment
C-Cystatin at the end of study	Plasma levels (AUC) of the early marker of kidney damage (C-Cystatin) changes from baseline	72 hours from enrollment
N-GAL at the end of study	Plasma levels (AUC) of the early marker of kidney damage (N-GAL) changes from baseline	72 hours from enrollment
Kidney Function at the end of study	Estimated Glomerular Filtration Rate (eGFR) change from baseline (Median (IQR))	72 hours from enrollment
Lorazepam Pharmacokinetics (Cmax)	Cmax of Lorazepam	72 hours from enrollment
Lorazepam Pharmacokinetics (Tmax)	Tmax of Lorazepam	72 hours from enrollment
Lorazepam Pharmacokinetics (Drug Clearance)	Drug clearance (CL)	72 hours from enrollment
Lorazepam Pharmacokinetics (Half Life)	Half life (t1/2) of Lorazepam	72 hours from enrollment
Lorazepam Pharmacokinetics (Cmin)	Cmin of Lorazepam	72 hours from enrollment

Collaborators and Investigators

• Sponsor: Bambino Gesù Hospital and Research Institute
• Collaborators: University College, London; Ministero della Salute, Italy
• Investigators: Principal Investigator: Marco Marano, MD, Bambino Gesù Hospital and Research Institute

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2020
• Primary Completion (Anticipated): July 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: June 18, 2020
• First Submitted That Met QC Criteria: November 20, 2020
• First Posted (Actual): November 27, 2020

Study Record Updates

• Last Update Posted (Actual): November 27, 2020
• Last Update Submitted That Met QC Criteria: November 20, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Mechanical Ventilation; Intensive Care; Lorazepam; Analgosedation; Propylene Glycol
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticonvulsants; Lorazepam
• Other Study ID Numbers: 1954 / 2019; 2019-003901-93 (EudraCT Number)

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