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

Department of Pediatrics, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
Pediatric Critical Care Medicine (Impact Factor: 2.34). 11/2010; 13(1):e48-50. DOI: 10.1097/PCC.0b013e3181fe406d
Source: PubMed


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.
Analysis of prospectively collected pharmacokinetic and pharmacodynamic data from a midazolam study in critically ill children.
Pediatric intensive care unit of a university hospital.
Twenty-one critically ill children who needed midazolam for sedation.
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.
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.

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    • "Besides developmental influences, neonatal and pediatric intensive care patients' clinical conditions also contribute to changes in pharmacokinetics and pharmacodynamics, and may increase the unpredictability of the patient's response to midazolam dosing. Changes in pharmacokinetics due to critical illness can include a slower metabolism or renal excretion, caused by an impaired hepatic or renal function, or an altered midazolam distribution due to decreased albumin binding and an increased volume of distribution due to oedema or sepsis [64]. Also, although less clear, pharmacodynamics can be altered during critical illness, manifesting itself in more side effects or more difficulties in achieving therapeutic effect. "
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    ABSTRACT: A variety of developmental changes is of influence on the pharmacokinetics and pharmacodynamics of midazolam in neonatal and pediatric intensive care patients. However, dosing regimens in children are based upon rather empirical extrapolations from the dosing regimens in adults. Based on current available studies it appears that with the rising of age, the pharmacokinetics of intravenously administered midazolam alter, resulting in a shorter half-life due to a higher hepatic clearance in older children as compared to newborn. Also, with the rising of age, the pharmacodynamics of intravenously administered midazolam may alter due to a decrease in density of receptors, possibly leading to a decreased clinical response. These findings implicate opposite effects and it is uncertain which of these effects are predominant. In conclusion, there is a large interindividual variability in the response to midazolam in children, which may be caused by differences in pharmacokinetics and pharmacodynamics. Both are subject to considerable developmental changes. It remains remarkable that high-quality evidence to support the use of midazolam for continuous sedation in the neonatal and pediatric intensive care setting is lacking.
    Current Drug Metabolism 03/2012; 13(6):760-6. DOI:10.2174/138920012800840347 · 2.98 Impact Factor
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    ABSTRACT: Inflammation is involved in the pathogenesis of cardiovascular diseases that includes reduced response to pharmacotherapy due to altered pharmacokinetics and pharmacodynamics. It is not known if these effects exist in general in all inflammatory conditions. It also remains unknown whether in a given population the effect is a function of disease severity. We investigated whether pharmacokinetics and pharmacodynamics of a typical calcium channel inhibitor are influenced by Crohn's disease (CD), a disease for which the disease severity can be readily ranked. We administered 80 mg verapamil orally to (i) healthy control subjects (n= 9), (ii) patients with clinically quiescent CD (n= 22) and (iii) patients with clinically active CD (n= 14). Serial analysis of verapamil enantiomers (total and plasma unbound), blood pressure and electrocardiograms were recorded over 8 h post dose. The severity of CD was measured using the Harvey-Bradshaw Index. CD substantially and significantly increased plasma verapamil concentration and in a stereoselective fashion (S, 9-fold; R, 2-fold). The elevated verapamil concentration, however, failed to result in an increased verapamil pharmacodynamic effect so that the patients with elevated verapamil concentration demonstrated no significant increase in response measured as PR interval and blood pressure. Instead, the greater the disease severity, the lower was the drug potency to prolong PR interval (r= 0.86, P < 0.0006), CD patients with severe disease may not respond to cardiovascular therapy with calcium channel blockers. Reducing the severity increases response despite reduced drug concentration. This observation may have therapeutic implication beyond the disease and the drug studies herein.
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