Population pharmacokinetics and haemodynamic effects of norepinephrine in hypotensive critically ill children

Aim

The aim of the study was to investigate the pharmacokinetics and pharmacodynamics of norepinephrine in hypotensive critically ill children, including associated variability factors.

Methods

This was a prospective study in an 18-bed neonatal and paediatric intensive care unit. All children were aged less than 18 years, weighed more than 1500 g and required norepinephrine for systemic arterial hypotension. The pharmacokinetics and haemodynamic effects were described using the non-linear mixed effect modelling software MONOLIX.

Results

Norepinephrine dosing infusions ranging from 0.05 to 2 μg kg⁻¹ min⁻¹ were administered to 38 children whose weight ranged from 2 to 85 kg. A one compartment open model with linear elimination adequately described the norepinephrine concentration–time courses. Bodyweight (BW) was the main covariate influencing norepinephrine clearance (CL) and endogenous norepinephrine production rate (q0) via an allometric relationship: CL(BWi) = θ_CL × (BWi)^3/4 and q0(BWi) = θ_q0 × (BWi)^3/4. The increase in mean arterial pressure (MAP) as a function of norepinephrine concentration was well described using an E_max model. The effects of post-conceptional age (PCA) and number of organ dysfunctions were significant on basal MAP level (MAP_0i = MAP₀ × PCA/9_i^0.166) and on the maximal increase in MAP (32 mmHg and 12 mmHg for a number of organ dysfunctions ≤3 and ≥4, respectively).

Conclusion

The pharmacokinetics and haemodynamic effects of norepinephrine in hypotensive critically ill children highlight the between-subject variability which is related to the substantial role of age, BW and severity of illness. Taking into account these individual characteristics may help clinicians in determining an appropriate initial a priori dosing regimen.     

Safety and immunogenicity of SC599, an oral live attenuated Shigella dysenteriae type-1 vaccine in healthy volunteers: Results of a Phase 2, randomized,double-blind placebo-controlled trial

SC599 vaccine is a live Shigella dysenteriae 1 strain attenuated by deletion of invasion [icsA], iron chelation [ent, fep] and shiga toxin A subunit [stxA] genes. In a preliminary Phase 1 single dose prospective study, we showed that SC599 vaccine was well tolerated, and the maximum tolerable dose was greater than 10⁸ CFU [Sadorge C, Ndiaye A, Beveridge N, Frazer S, Giemza R, Jolly N, et al. Phase 1 clinical trial of live attenuated Shigella dysenteriae type-1 ΔicsA Δent Δfep ΔstxA:HgR oral vaccine SC599 in healthy human adult volunteers. Vaccine 2008; 26(7):978–8]. In this Phase 2 trial, three groups of volunteers ingested a single dose of SC599 [10⁵ CFU, n = 38; 10⁷ CFU, n = 36] or placebo [n = 37]. Both 10⁵ and 10⁷ CFU doses were immunogenic, inducing significant IgA and IgG LPS-specific ASCs and antibody responses, comparable in magnitude to those of other strains that prevented illness following experimental challenge. In the intention to treat analysis, 34.2% and 44.4% IgA ASC responders were detected in the 10⁵ and 10⁷ CFU groups respectively (p < 0001 vs placebo for both groups), as well as 31.6% and 33.3% serum IgA responders (p < 001 and p < 0.001 vs placebo for 10⁵ and 10⁷ CFU groups, respectively). No difference between the two vaccine groups was observed. No stxB-specific antibody response was detected in the vaccines. SC599 excretion occurred in 23.7 and 30.6% of subjects in the 10⁵ and 10⁷ CFU groups, respectively. SC599 vaccine was well tolerated, and the reported adverse events were mainly digestive. These results indicate that a single oral immunization of SC599 vaccine elicits a significant circulating IgA ASC and serum antibody response that may confer protection against the most severe symptoms of Shigellosis in responders to the vaccine.     

A New Intravenous Fat Emulsion Containing Soybean Oil,Medium‐Chain Triglycerides,Olive Oil,and Fish Oil

Background: SMOFlipid 20% is an intravenous lipid emulsion (ILE) containing soybean oil, medium‐chain triglycerides, olive oil, and fish oil developed to provide energy, essential fatty acids (FAs), and long‐chain ω‐3 FAs as a mixed emulsion containing α‐tocopherol. The aim was to assess the efficacy and safety of this new ILE in pediatric patients receiving home parenteral nutrition (HPN) compared with soybean oil emulsion (SOE). Methods: This single‐center, randomized, double‐blind study included 28 children on HPN allocated to receive either SMOFlipid 20% (n = 15) or a standard SOE (Intralipid 20%, n = 13). ILE was administered 4 to 5 times per week (goal dose, 2.0 g/kg/d) within a parenteral nutrition regimen. Assessments, including safety and efficacy parameters, were performed on day 0 and after the last study infusion (day 29). Lipid peroxidation was determined by measurement of thiobarbituric acid reactive substances (TBARS). Results: There were no significant differences in laboratory safety parameters, including liver enzymes, between the groups on day 29. The mean ± standard deviation changes in the total bilirubin concentration between the initial and final values (day 29 to day 0) were significantly different between groups: SMOFlipid group ?1.5 ± 2.4 µmol/L vs SOE group 2.3 ± 3.5 µmol/L, P < .01; 95% confidence interval [CI], ?6.2 to ?1.4). In plasma and red blood cell (RBC) phospholipids, the ω‐3 FAs C20:5ω‐3 (eicosapentaenoic acid) and + C22:6ω‐3 (docosahexaenoic acid) increased significantly in the SMOFlipid group on day 29. The ω‐3:ω‐6 FA ratio was significantly elevated with SMOFlipid 20% compared with SOE group (plasma, day 29: 0.15 ± 0.06 vs 0.07 ± 0.02, P < .01, 95% CI, 0.04–0.11; and RBC, day 29: 0.23 ± 0.07 vs 0.14 ± 0.04, P < .01, 95% CI, 0.04–0.13). Plasma α‐tocopherol concentration increased significantly more with SMOFlipid 20% (15.7 ± 15.9 vs 5.4 ± 15.2 µmol/L, P < .05; 95% CI, ?2.1 to 22.6). The low‐density lipoprotein–TBARS concentrations were not significantly different between both groups, indicating that lipid peroxidation did not differ between groups. Conclusions: SMOFlipid 20%, which contains 15% fish oil, was safe and well tolerated, decreased plasma bilirubin, and increased ω‐3 FA and α‐tocopherol status without changing lipid peroxidation.     

A point mutation in the glycerol kinase gene associated with a deletion in the dystrophin gene in a familial X-linked muscular dystrophy: non-contiguous gene syndrome involving Becker muscular dystrophy and glycerol kinase loci

We report a family with an X-linked recessive muscular dystrophy characterised by exercise-induced myalgia, recurrent pigmenturia and mild proximal muscle involvement. Immunocytochemical and immunoblotting analysis in muscle, using the antibody directed against the rod domain of dystrophin, revealed a loss of immunoreactivity, but the immunolabelling using the antibodies directed against the COOH and NH₂ domains of dystrophin were almost normal. The immunoreactions for -sarcoglycan, γ-sarcoglycan and β-dystroglycan were normal. In the five male patients of this family with increased serum creatine kinase levels (from ×8 to ×50), mass spectrometry screening of the urine revealed a large increase in glycerol elimination which was quantified by enzymatic assay (from ×14 to ×39). An in-frame deletion of the dystrophin gene (exons 13–29) was found in the same five males and in three carrier females. All the deleted chromosomes also carried a missense mutation at nucleotide 947 of the Xp glycerol kinase (GK) gene resulting in a Thr to Met substitution at codon 278. These findings indicate that the two mutations cosegregate on the same chromosome in this family. This is the first reported case of two physically independent mutations, within the DMD and GK genes, which are contiguous but several hundred kilobases apart.     

Effects of tetrabamate and of diazepam on sleep polygraphy during subacute withdrawal in alcohol-dependent patients

We have studied the effects of two anxiolytic drugs frequently prescribed in alcohol withdrawal, diazepam and tetrabamate, on sleep polygraphy of alcohol-dependent patients hospitalized for alcohol detoxification. Twenty-three inpatients (16 M and 7F) fulfilling the DSM 3R alcohol-dependence criteria were included. Twelve patients were treated with tetrabamate and the other 11 with diazepam. Sleep polygraphy was carried out on average 15 days after alcohol withdrawal. The sleep of tetrabamate-treated patients differs from that of diazepam-treated patients in having a much longer duration of stage 4, at the expense mainly of stage 2. The two groups of patients had a greater total sleep time and duration of delta sleep than comparable untreated patients. These results suggest that the delta sleep deficit of abstinent alcoholics is paradoxically corrected by anxiolytic treatment. Tetrabamate seems to induce the production of delta waves during the sleep of abstinent alcoholics.     

Human allograft vein failure: Immunohistochemical arguments supporting the involvement of an immune-mediated mechanism

The aim of this study was to search for signs suggestive of an ongoing immune-mediated reaction in failed human cryopreserved venous allografts. In 15 samples, the authors analyzed: (1) the pattern of morphological changes; (2) the density, distribution, and phenotype of leukocytic infiltrate; and (3) the expression of class II major histocompatibility complex (MHC) antigens and inducible adhesion molecules. Two groups of samples could be recognized. In samples explanted before 3 months after grafting, the structure of the vessel wall was preserved. A dense leukocytic infiltrate was present within the intima and around the numerous vasa vasorum located in medial and adventitial layers. Class II MHC antigens and cytokine-dependent molecules were induced on endothelial cells lining the vasa vasorum and on residual smooth muscle cells. In samples explanted after 3 months of evolution, the vessel wall has lost its normal structure and contained few vasa vasorum. A few leukocytes were detected around capillary vessels located in the peripheral connective tissue surrounding the graft. Class H MHC antigens and adhesion molecules were induced on endothelial cells lining the peripheral capillary vessels. These results suggest the involvement of an immune-mediated mechanism at the early stage of the evolution of failed human venous allografts.     

Dementia disclosing primary Gougerot-Sj?gren syndrome]

Two cases of primary Sj?gren's syndrome revealed by dementia are reported. The patients had progressive or subacute memory dysfunction and psychiatric disorders with depression and delirium. The diagnosis of Sj?gren's syndrome was established by biopsy of the minor salivary glands. Both patients were treated with corticosteroids. The neuropsychiatric symptoms improved dramatically in one case and remained unchanged in the other case. Dementia in Sj?gren's syndrome seems to be without aphasia, apraxia or agnosia, and associated with psychiatric features, particularly depressive symptoms, thus including some characteristics of subcortical dementia. Diagnosis may be difficult because, as shown in our cases, symptoms of ocular and buccal dryness can be absent. Salivary gland biopsy can be useful in the evaluation of patients with dementia of undetermined etiology.     

Two co-existing mechanisms account for the large-scale deletions of mitochondrial DNA in Podospora anserina that involve the 5′ border of a group-II intron

A degenerative syndrome associated with the accumulation of site-specific deletions within mitochondrial chromosomes occurs in strains of Podospora anserina carrying the AS1-4 nuclear mutation. The site-specific deletion event has been assumed to result from the transposition of a group-II intron (intron α) behind an IBS motif, followed by recombination between the two intron repeats. We show here that a number of distinct deletions can accumulate in AS1-4 strains. Most of them are present in low amounts in wild-type cells where they are only detectable in PCR experiments. The deletions can be divided into two classes. In class I, intron α is joined to an IBS motif. In class II, the intron is not joined to an IBS site, it can be truncated or contain a few upstream exonic nucleotides; some junctions carry non-templated nucleotides. These results indicate that at least two mechanisms are involved in the generation of large-scale mitochondrial deletions in Podospora. One of them seems to be based on the transposition properties of the group-II α intron, the other one on illegitimate recombination. We propose that these two mechanisms use DNA double-strand breaks occurring within the 5′ region of intron α. Received: 15 May / 18 August 1998     

Pseudo-outbreak of Pseudomonas aeruginosa and Serratia marcescens related to bronchoscopes.

OBJECTIVE: To investigate an apparent outbreak involving simultaneous isolation of Pseudomonas aeruginosa and Serratia marcescens from bronchoalveolar lavage (BAL) samples. DESIGN: Retrospective and prospective cohort studies using chart review, environmental sampling, and ribotyping of all available isolates. Cleaning and disinfection procedures for the bronchoscopes were also evaluated. SETTING: A 380-bed private hospital in S?o Paulo, Brazil PATIENTS: Forty-one patients who underwent bronchoscopic procedures between December 1994 and October 1996 and from whom P. aeruginosa and S. marcescens were concomitantly isolated. Bronchoscopes and related items were microbiologically assessed. RESULTS: P. aeruginosa and S. marcescens were simultaneously isolated from BAL samples 12.6% of the time (41 of 324) during the epidemic period versus 1.8% of the time (1 of 54) in the pre-epidemic period (P = .035). Ribotyping revealed two strains of P. aeruginosa and one of S. marcescens that were isolated from BAL samples of patients with no signs of respiratory tract infection, suggesting a pseudo-outbreak. Evaluation of bronchoscope disinfection revealed that inappropriate methods were being used. Implementation of simple control measures resulted in a significant decrease in simultaneous isolation of these species. CONCLUSION: Prevention of pseudo-outbreaks requires meticulous use of preventive measures for infection-prone medical procedures.