Lorazepam for the Analgosedation of Pediatric Patients in Mechanical Ventilation.

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Analgesia

Intervention / Treatment
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* Drug: Lorazepam 4 mg/ml


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 11 Years

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Arm I: Day 1: 6 Boluses at 0.1 mg/kg LZ every 4 hr Day 2: 6 Boluses at 0.2 mg/kg LZ every 4 hr Day 3: Continuous Infusion at 0.025 mg/kg/hr LZ Arm II: Day 1: 6 Boluses at 0.2 mg/kg LZ every 4 hr Day 2: 6 Boluses at 0.1 mg/kg LZ every 4 hr Day 3: Continuous Infusion at 0.03 mg/kg/hr LZ Arm III: Day 1: 6 Boluses at 0.3 mg/kg LZ every 4 hr Day 2: 6 Boluses at 0.1 mg/kg LZ every 4 hr Day 3: Continuous Infusion at 0.025 mg/kg/hr LZ Patients will be monitored for further 3 days of follow-up, after the end of the administration sequence. In case they would still need to undergo analgosedation, other drugs will be administered (e.g. midazolam, dexmedetomidine). Patients will also be divided into two age groups - 6 patients: age ≥1 year <5 years (COHORT 1); 3 patients: age ≥5 years - <12 years (COHORT 2)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence 1<br>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<br>* Lorazepam will be administered intravenously according to the scheduled sequences.<br>|
| Experimental: Sequence 2<br>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<br>* Lorazepam will be administered intravenously according to the scheduled sequences.<br>|
| Experimental: Sequence 3<br>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<br>* Lorazepam will be administered intravenously according to the scheduled sequences.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lorazepam, Intensive Care, Analgosedation, Mechanical Ventilation, Propylene Glycol