Drug Therapy in Critically Ill Children

Although widely prescribed, the safety and efficacy of drugs administered to critically ill children is hardly studied in this population. In addition to the age-related maturation of drug-metabolizing enzymes and renal function, acute illness and its treatment modalities may also impact drug disposition and response. More evidence based dosing regimens can be derived only if the effect of factors such as inflammation and disease state on pharmacokinetics as well as pharmacodynamics is known. The aims of this thesis were: 1. To study the influence of critical illness (inflammation and disease state) in children on midazolam pharmacokinetics, as a surrogate measure of CYP3A activity. 2. To study the safety and efficacy of daily sedation interruption in critically ill children

Application to Add Midazolam to the Model List of Essential Medicines

Summary statement of the proposal for inclusion The benzodiazepine midazolam has proven sedative, anxiolytic and amnesic properties. It is extensively used for premedication and procedural sedation in both adults and children. In comparison to other benzodiazepine and non-benzodiazepine drugs, midazolam is equally or more effective for premedication/preoperative sedation. No evidence exists that premedication with midazolam prolongs discharge time from hospital. Its efficacy and safety have been extensively studied in both adults and children. This contrasts its comparator drug, diazepam for which data in children and elderly are scarce or lacking. Midazolam is also effective for procedural sedation as a single drug or in combination with an opioid. As a single drug, adequate sedation for procedures in the emergency room, is achieved in over 90% of all procedures. Comparative efficacy was shown for propofol. Data are insufficient to determine comparative efficacy for procedural sedation for other drugs. When administered with the appropriate precautions, e.g. titration to effect, adequate monitoring and personnel to support ventilation, midazolam is very safe. No major adverse events were seen in 847 adults who received midazolam for procedural sedation. Also, adverse effects can be antagonized with an effective antagonist, flumazenil. As midazolam is off-patent, drug costs are relatively low. Drug costs per procedure range from approximately 0.15 US$to 2.6 US$ in an adult, depending on dose and country, with significantly lower costs in developing countries

Striving for an effective but parsimonious use of sedation in pediatric intensive care

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A randomized controlled trial of daily sedation interruption in critically ill children

Purpose: To compare daily sedation interruption plus protocolized sedation (DSI + PS) to protocolized sedation only (PS) in critically ill children. Methods: In this multicenter randomized controlled trial in three pediatric intensive care units in the Netherlands, mechanically ventilated critically ill children with need for sedative drugs were included. They were randomly assigned to either DSI + PS or PS only. Children in both study arms received sedation adjusted on the basis of validated sedation scores. Provided a safety screen was passed, children in the DSI + PS group received daily blinded infusions of saline; children in the PS group received blinded infusions of the previous sedatives/analgesics. If a patient’s sedation score indicated distress, the blinded infusions were discontinued, a bolus dose of midazolam was given and the ‘open’ infusions were resumed: DSI + PS at half of infusion rate, PS at previous infusion rate. The primary endpoint was the number of ventilator-free days at day 28. Data were analyzed by intention to treat. Results: From October 2009 to August 2014, 129 children were randomly assigned to DSI + PS (n = 66) or PS (n = 63). The study was terminated prematurely due to slow recruitment rates. Median number of ventilator-free days did not differ: DSI + PS 24.0 days (IQR 21.6–25.8) versus PS 24.0 days (IQR 20.6–26.0); median difference 0.02 days (95 % CI −0.91 to 1.09), p = 0.90. Median ICU and hospital length of stay were similar in both groups: DSI + PS 6.9 days (IQR 5.2–11.0) versus PS 7.4 days (IQR 5.3–12.8), p = 0.47, and DSI + PS 13.3 days (IQR 8.6–26.7) versus PS 15.7 days (IQR 9.3–33.2), p = 0.19, respectively. Mortality at 30 days was higher in the DSI + PS group than in the PS group (6/66 versus 0/63, p = 0.03), though no causal relationship to the intervention could be established. Median cumulative midazolam dose did not differ: DSI + PS 14.1 mg/kg (IQR 7.6–22.6) versus PS 17.0 mg/kg (IQR 8.2–39.8), p = 0.11. Conclusion: In critically ill children, daily sedation interruption in addition to protocolized sedation did not improve clinical outcome and was associated with increased mortality compared with protocolized sedation only

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure

Aims: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice. Methods: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l-1 and 0-4 failing organs) using graphical and numerical diagnostics. Results: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) 180%). Conclusion: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates

Daily interruption of sedation in critically ill children: Study protocol for a randomized controlled trial

Background: In adult patients who are critically ill and mechanically ventilated, daily interruption of sedation (DSI) is an effective method of improving sedation management, resulting in a decrease of the duration of mechanical ventilation, the length of stay in the intensive care unit (ICU) and the length of stay in the hospital. It is a safe and effective approach and is common practice in adult ICUs. For critically ill children it is unknown if DSI is effective and feasible. The aim of this multicenter randomized controlled trial is to evaluate the safety and

Population Pharmacokinetics of Intravenous Salbutamol in Children with Refractory Status Asthmaticus

Background: Intravenous salbutamol is used to treat children with refractory status asthmaticus, however insufficient pharmacokinetic data are available to guide initial and subsequent dosing recommendations for its intravenous use. The pharmacologic activity of salbutamol resides predominantly in the (R)-enantiomer, with little or no activity and even concerns of adverse reactions attributed to the (S)-enantiomer. Objective: Our aim was to develop a population pharmacokinetic model to characterize the pharmacokinetic profile for intravenous salbutamol in children with status asthmaticus admitted to the pediatric intensive care unit (PICU), and to use this model to study the effect of different dosing schemes with and without a loading dose. Methods: From 19 children (median age 4.9 years [range 9 months–15.3 years], median weight 18 kg [range 7.8–70 kg]) treated with continuous intravenous salbutamol at the PICU, plasma samples for R- and S-salbutamol concentrations (111 samples), as well as asthma scores, were collected prospectively at the same time points. Possible adverse reactions and patients’ clinical data (age, sex, weight, drug doses, liver and kidney function) were recorded. With these data, a population pharmacokinetic model was developed using NONMEM 7.2. After validation, the model was used for simulations to evaluate the effect of different dosing regimens with or without a loading dose. Results: A two-compartment model with separate clearance for R- and S-salbutamol (16.3 L/h and 8.8 L/h, respectively) best described the data. Weight was found to be a significant covariate for clearance and volume of distribution. No other covariates were identified. Simulations showed that a loading dose can result in higher R-salbutamol concentrations in the early phase after the start of infusion therapy, preventing accumulation of S-salbutamol. Conclusions: The pharmacokinetic model of intravenous R- and S-salbutamol described the data well and showed that a loading dose should be considered in children. This model can be used to evaluate the pharmacokinetic–pharmacodynamic relationship of intravenous salbutamol in children, and, as a next step, the effectiveness and tolerability of intravenous salbutamol in children with severe asthma

The effect of critical illness and inflammation on midazolam therapy in children

OBJECTIVE:: To determine the effect of inflammation and disease severity on midazolam pharmacokinetics (as surrogate marker of cytochrome 3A activity) and pharmacodynamics in critically ill children. DESIGN:: Analysis of prospectively collected pharmacokinetic and pharmacodynamic data from a midazolam study in critically ill children. SETTING:: Pediatric intensive care unit of a university hospital. PATIENTS:: Twenty-one critically ill children who needed midazolam for sedation. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: We determined the relationship between inflammation (using C-reactive protein and leukocyte count as surrogate markers) and disease severity (Pediatric Logistic Organ Dysfunction and Pediatric Risk of Mortality scores) vs. the pharmacokinetics (clearance) and pharmacodynamics (COMFORT score, dose requirement) of midazolam. We found a significant negative correlation between disease severity and midazolam clearance corrected for body weight (r =-0.49, p = .02). Midazolam clearance was significantly lower in children with multiple organ failure (defined as Pediatric Logistic Organ Dysfunction ≥10, n = 11) compared with children without multiple organ failure (Pediatric Logistic Organ Dysfunction <10, n = 10) (median 0.14 [interquartile range, 0.11-0.23] vs. 0.28 [interquartile range, 0.14-0.43]) L/kg/h, p = .035). No other significant correlations were found. CONCLUSIONS:: Results from this pilot study suggest that increased disease severity is associated with reduced midazolam clearance in critically ill children, most likely as a result of reduced cytochrome 3A activity. In contrast, reduced midazolam clearance does not seem to result in decreased midazolam dose requirements

The effect of inflammation on drug metabolism: A focus on pediatrics

Inflammation is associated with downregulation of the expression and activity of cytochrome P450 enzymes (CYP450) involved in hepatic drug metabolism. Elevated plasma drug levels and increased toxicity might be the consequences of this downregulation. Few clinical studies have investigated these consequences of inflammation in children, who are prescribed many off-label or unlicensed drugs. This review describes the impact of inflammation on CYP450 drug metabolism and drug effect in children, with the consequent implications for drug studies and clinical therapy in this group