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.
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
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
NONE
Enrollment
9
Lorazepam will be administered intravenously according to the scheduled sequences.
Lorazepam Pharmacokinetics (AUC)
AUC of Lorazepam
Time frame: 72 hours from enrollment
Analgosedative efficacy of Lorazepam
Frequency of responder patients (COMFORT-B scale score between 11 and 22 and alertness score between 2 and 3)
Time frame: 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.
Time frame: 72 hours from enrollment
Dropouts due to any adverse event
Number of interruptions of the experimental administration sequence due to adverse events
Time frame: 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
Time frame: 72 hours from enrollment
AEs/SAEs registration at end of follow-up
Number of AEs / SAEs at the end of the follow-up period
Time frame: 6 days from enrollment
Vital signs at the end of study (Blood Pressure)
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Blood Pressure measurement in mmHg, change from baseline (Median (IQR))
Time frame: 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))
Time frame: 72 hours from enrollment
Vital signs at the end of study (Body Temperature)
Body temperature measurement in °C, change from baseline (Median (IQR))
Time frame: 72 hours from enrollment
Vital signs at the end of follow-up (Blood Pressure)
Blood Pressure measurement in mmHg, change from baseline (Median (IQR))
Time frame: 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))
Time frame: 6 days from enrollment
Vital signs at the end of follow-up (Body Temperature)
Body temperature measurement in °C, change from baseline (Median (IQR))
Time frame: 6 days from enrollment
Plasma concentrations of Propylene Glycol at the end of study
AUC of PG in mg/L in serum
Time frame: 72 hours from enrollment
Osmol gap at the end of study
Osmol gap (detected osmolarity - calculated osmolarity) change from baseline (Median (IQR)
Time frame: 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
Time frame: 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
Time frame: 72 hours from enrollment
Kidney Function at the end of study
Estimated Glomerular Filtration Rate (eGFR) change from baseline (Median (IQR))
Time frame: 72 hours from enrollment
Lorazepam Pharmacokinetics (Cmax)
Cmax of Lorazepam
Time frame: 72 hours from enrollment
Lorazepam Pharmacokinetics (Tmax)
Tmax of Lorazepam
Time frame: 72 hours from enrollment
Lorazepam Pharmacokinetics (Drug Clearance)
Drug clearance (CL)
Time frame: 72 hours from enrollment
Lorazepam Pharmacokinetics (Half Life)
Half life (t1/2) of Lorazepam
Time frame: 72 hours from enrollment
Lorazepam Pharmacokinetics (Cmin)
Cmin of Lorazepam
Time frame: 72 hours from enrollment