Clinical trial NCT04646135: Lorazepam for the Analgosedation of Pediatric Patients in Mechanical Ventilation.
Official title: 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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Analgesia
Keywords: Lorazepam
Intensive Care
Analgosedation
Mechanical Ventilation
Propylene Glycol
Lead sponsor: Bambino Gesù Hospital and Research Institute
Sponsor class: OTHER
Collaborators: name: Ministero della Salute, Italy
name: University College, London
First posted: 2020-11-27
Enrollment: 9
Sex: ALL
Minimum age (years): 1
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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)
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Lorazepam Pharmacokinetics (AUC)
timeFrame: 72 hours from enrollment
Secondary outcomes:
measure: Analgosedative efficacy of Lorazepam
timeFrame: 72 hours from enrollment
measure: COMFORT-BEHAVIOURAL (COMFORT-B) scale
timeFrame: 72 hours from enrollment
measure: Dropouts due to any adverse event
timeFrame: 72 hours from enrollment
measure: Adverse Events (AEs)/ Serious Adverse Events (SAEs) registration at end of study
timeFrame: 72 hours from enrollment
measure: AEs/SAEs registration at end of follow-up
timeFrame: 6 days from enrollment
measure: Vital signs at the end of study (Blood Pressure)
timeFrame: 72 hours from enrollment
measure: Vital signs at the end of study (Heart Rate)
timeFrame: 72 hours from enrollment
measure: Vital signs at the end of study (Body Temperature)
timeFrame: 72 hours from enrollment
measure: Vital signs at the end of follow-up (Blood Pressure)
timeFrame: 6 days from enrollment
measure: Vital signs at the end of follow-up (Heart Rate)
timeFrame: 6 days from enrollment
measure: Vital signs at the end of follow-up (Body Temperature)
timeFrame: 6 days from enrollment
measure: Plasma concentrations of Propylene Glycol at the end of study
timeFrame: 72 hours from enrollment
measure: Osmol gap at the end of study
timeFrame: 72 hours from enrollment
measure: C-Cystatin at the end of study
timeFrame: 72 hours from enrollment
measure: N-GAL at the end of study
timeFrame: 72 hours from enrollment
measure: Kidney Function at the end of study
timeFrame: 72 hours from enrollment
measure: Lorazepam Pharmacokinetics (Cmax)
timeFrame: 72 hours from enrollment
measure: Lorazepam Pharmacokinetics (Tmax)
timeFrame: 72 hours from enrollment
measure: Lorazepam Pharmacokinetics (Drug Clearance)
timeFrame: 72 hours from enrollment
measure: Lorazepam Pharmacokinetics (Half Life)
timeFrame: 72 hours from enrollment
measure: Lorazepam Pharmacokinetics (Cmin)
timeFrame: 72 hours from enrollment
Other outcomes:
Locations:
Study officials:
affiliation: Bambino Gesù Hospital and Research Institute
name: Marco Marano, MD
role: PRINCIPAL_INVESTIGATOR
References: