Gamma-hydroxybutyrate: is it a feasible alternative to midazolam in long-term mechanically ventilated children?

Aim: Benzodiazepines like midazolam are commonly used for long-term sedation of critically ill children requiring mechanical ventilation. Tolerance to midazolam may occur in these patients resulting in a ceiling effect with insufficient or missing sedative response to increases of midazolam infusion or bolus application. The aim of this study was to evaluate the feasibility of a drug rotation protocol replacing continuous infusion of midazolam with gamma-hydroxybutyrate (GHB) to counteract midazolam tolerance. Methods: This retrospective, observational study was conducted in a 14-bed pediatric intensive care unit of a tertiary referral center. Thirty-three mechanically ventilated children with tolerance to midazolam who received continuous infusion of GHB were included. Success of drug rotation from midazolam to GHB was defined as adequate sedation with GHB and subsequent reduction of required doses of midazolam. Results: In our cohort, drug rotation for at least 2 days could be successfully performed in 10 out of 34 children resulting in subsequent reduction of required doses of midazolam. Drug rotation to GHB failed in 24 patients due to insufficient sedation resulting in a premature termination of the protocol. In these children, dosing of midazolam could not be reduced following drug rotation. We could not identify factors which predict success or failure of drug rotation from midazolam to GHB. Conclusions: The data from our single-center study suggest that drug rotation from midazolam to GHB may be worth trying in children with midazolam tolerance during long-term sedation, but physicians should be aware of possible treatment failure.

Complementation studies of the Arabidopsis fc1 mutant substantiate essential functions of ferrochelatase 1 during embryogenesis and salt stress.

Ferrochelatase (FC) is the final enzyme for haem formation in the tetrapyrrole biosynthesis pathway and encoded by two genes in higher plants. FC2 exists predominantly in green tissue, whereas FC1 is constitutively expressed. We intended to substantiate the specific roles of FC1. The embryo-lethal fc1-2 mutant was used to express the two genomic FC-encoding sequences under the FC1 and FC2 promoter and explore the complementation of the FC1 deficiency. Apart from the successful complementation with FC1, expression of FC2 under control of the FC1 promoter (pFC1::FC2) compensates for missing FC1 but not by FC2 promoter expression. The complementing lines pFC1FC2(fc1/fc1) succeeded under standard growth condition but failed under salt stress. The pFC1FC2(fc1/fc1) line exhibited symptoms of leaf senescence, including accelerated loss of haem and chlorophyll and elevated gene expression for chlorophyll catabolism. In contrast, ectopic FC1 expression (p35S::FC1) resulted in increased chlorophyll accumulation. The limited ability of FC2 to complement fc1 is explained by a faster turnover of FC2 mRNA during stress. It is suggested that FC1-produced haem is essential for embryogenesis and stress response. The pFC1::FC2 expression readily complements the fc1-2 embryo lethality, whereas higher FC1 transcript content contributes essentially to stress tolerance.