The effect of giving influenza vaccination to general practitioners: a controlled trial [NCT00221676]

BACKGROUND: No efficacy studies of influenza vaccination given to GPs have yet been published. Therefore, our purpose was to assess the effect of an inactivated influenza vaccine given to GPs on the rate of clinical respiratory tract infections (RTIs) and proven influenza cases (influenza positive nose and throat swabs and a 4-fold titre rise), while adjusting for important covariates. METHODS: In a controlled trial during two consecutive winter periods (2002–2003 and 2003–2004) we compared (77 and 100) vaccinated with (45 and 40) unvaccinated GPs working in Flanders, Belgium. Influenza antibodies were measured immediately prior to and 3–5 weeks after vaccination, as well as after the influenza epidemic. During the influenza epidemic, GPs had to record their contact with influenza cases and their own RTI symptoms every day. If they became ill, the GPs had to take nose and throat swabs during the first 4 days. We performed a multivariate regression analysis for covariates using Generalized Estimating Equations. RESULTS: One half of the GPs (vaccinated or not) developed an RTI during the 2 influenza epidemics. During the two influenza periods, 8.6% of the vaccinated and 14.7% of the unvaccinated GPs had positive swabs for influenza (RR: 0.59; 95%CI: 0.28 – 1.24). Multivariate analysis revealed that influenza vaccination prevented RTIs and swab-positive influenza only among young GPs (ORadj: 0.35; 95%CI: 0.13 – 0.96 and 0.1; 0.01 – 0.75 respectively for 30-year-old GPs). Independent of vaccination, a low basic antibody titre against influenza (ORadj 0.57; 95%CI: 0.37 – 0.89) and the presence of influenza cases in the family (ORadj 9.24; 95%CI: 2.91 – 29) were highly predictive of an episode of swab-positive influenza. CONCLUSION: Influenza vaccination was shown to protect against proven influenza among young GPs. GPs, vaccinated or not, who are very vulnerable to influenza are those who have a low basic immunity against influenza and, in particular, those who have family members who develop influenza

Scaling beta-lactam antimicrobial pharmacokinetics from early life to old age

AIMS Beta-lactam dose optimization in critical care is a current priority. We aimed to review the pharmacokinetics (PK) of three commonly used beta-lactams (amoxicillin ± clavulanate, piperacillin-tazobactam and meropenem) to compare PK parameters reported in critically and noncritically ill neonates, children and adults, and to investigate whether allometric and maturation scaling principles could be applied to describe changes in PK parameters through life. METHODS A systematic review of PK studies of the three drugs was undertaken using MEDLINE and EMBASE. PK parameters and summary statistics were extracted and scaled using allometric principles to 70 kg individual for comparison. Pooled data were used to model clearance maturation and decline using a sigmoidal (Hill) function. RESULTS A total of 130 papers were identified. Age ranged from 29 weeks to 82 years and weight from 0.9-200 kg. PK parameters from critically ill populations were reported with wider confidence intervals than those in healthy volunteers, indicating greater PK variability in critical illness. The standard allometric size and sigmoidal maturation model adequately described increasing clearance in neonates, and a sigmoidal model was also used to describe decline in older age. Adult weight-adjusted clearance was achieved at approximately 2 years postmenstrual age. Changes in volume of distribution were well described by the standard allometric model, although amoxicillin data suggested a relatively higher volume of distribution in neonates. CONCLUSIONS Critical illness is associated with greater PK variability than in healthy volunteers. The maturation models presented will be useful for optimizing beta-lactam dosing, although a prospective, age-inclusive study is warranted for external validation

Mortality and readmission rates of patients discharged in-hours and out-of-hours from a British ICU over a 3-year period

Excess in-hospital mortality following out-of-hours ICU discharge has been reported worldwide. From preliminary data, we observed that magnitude of difference may be reduced when patients discharged for end-of-life care or organ donation are excluded. We speculated that these patients may be disproportionately discharged out-of-hours, biasing results. We now compare in-hospital mortality and ICU readmission rates following discharge in-hours and out-of-hours over 3 years, excluding discharges for organ donation or end-of-life care. This single-centre retrospective study includes patients discharged alive following ICU admission between 01/07/2015-31/07/2018, excluding readmissions and discharges for end-of-life care/organ donation. A multiple logistic regression model was fitted to estimate adjusted odds ratio of death following out-of-hours versus in-hours discharge. Characteristics and outcomes for both groups were compared. 4678 patients were included. Patients discharged out-of-hours were older (62 vs 59 years, p < 0.001), with greater APACHE II scores (15.7 vs 14.4, p < 0.001), length of ICU stay (3.25 vs 3.00 days, p = 0.01) and delays to ICU discharge (736 vs 489 min, p < 0.001). No difference was observed in mortality (4.6% vs 3.7%, p = 0.25) or readmission rate (4.1% vs 4.2%, p = 0.85). In the multiple logistic regression model out-of-hours discharge was not associated with in-hospital mortality (OR = 1.017, 95% CI 0.682-1.518, p = 0.93). Our findings present a possible explanation for reported excess mortality following out-of-hours ICU discharge, related to inclusion of organ donation and end-of-life care patients in data sets rather than standards of care delivered out-of-hours. We are not aware of any other studies investigating the influence of this group on reported post-ICU mortality rates

Xenobiotic metabolism: the effect of acute kidney injury on non-renal drug clearance and hepatic drug metabolism.

Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth

Airway glucose concentrations and effect on growth of respiratory pathogens in cystic fibrosis

AbstractBackgroundPulmonary decline accelerates in cystic fibrosis-related diabetes (CFRD) proportional to severity of glucose intolerance, but mechanisms are unclear. In people without CF, airway glucose (AG) concentrations are elevated when blood glucose (BG)≥8 mmol L−1 (airway threshold), and are associated with acquisition of respiratory infection.MethodsTo determine the relationship between BG and AG, 40 CF patients underwent paired BG and AG (nasal) measurements. Daily time with BG>airway threshold was compared in 10 CFRD, 10 CF patients with normal glucose tolerance (CF-NGT) and 10 healthy volunteers by continuous BG monitoring. The effect of glucose at airway concentrations on bacterial growth was determined in vitro by optical densitometry.ResultsAG was present more frequently (85%-vs.-19%, p<0.0001) and at higher concentrations (0.5–3 mmol L−1-vs.-0.5–1 mmol L−1, p<0.0001) when BG was ≥8 mmol L−1-vs.-<8 mmol L−1. Daily time with BG≥8 mmol L−1 was CFRD (49±25%), CF-NGT (6±5%), healthy volunteers (1±3%), p<0.0001. Staphylococcus aureus growth increased at ≥0.5 mmol L−1 (p=0.006) and Pseudomonas aeruginosa growth above 1–4 mmol L−1 glucose (p=0.039).ConclusionsBG≥8 mmol L−1 predicted elevated AG concentrations in CF, at least in nasal secretions. CFRD patients spent ∼ 50% day with BG>airway threshold, implying persistently elevated AG concentrations. Further studies are required to determine whether elevated airway glucose concentrations contribute to accelerated pulmonary decline in CFRD

Idiopathic pulmonary fibrosis associated with pulmonary vein thrombosis: a case report

BACKGROUND: Pulmonary vein thrombosis represents a potentially fatal disease. This syndrome may clinically mimic pulmonary embolism but has a different investigation strategy and prognosis. Pulmonary vein thrombosis is difficult to diagnose clinically and usually requires a combination of conventionally used diagnostic modalities. CASE PRESENTATION: The authors report a case of a 78-year-old previously healthy female presenting with collapse and shortness of breath. Serum biochemistry revealed acute kidney injury, positive D-dimmer's and increased C reactive protein. Chest radiography demonstrated volume loss in the right lung. The patient was started on antibiotics and also therapeutic doses of low molecular weight heparin. The working diagnosis included community acquired pneumonia & pulmonary embolism. A computed tomography pulmonary angiogram was performed to confirm the clinical suspicions of pulmonary embolism. This demonstrated a thrombus in the pulmonary vein, with associated fibrosis and volume loss of the right lower lobe. A subsequent thrombophilia screen revealed a positive lupus anticoagulant antibody and rheumatoid factor and also decreased anti thrombin III and protein C levels. The urine protein/creatinine ratio was found to be 553 mg/mmol. CONCLUSION: The diagnosis of this patient was therefore of idiopathic pulmonary fibrosis associated with pulmonary vein thrombosis. Whether or not the pulmonary vein thrombosis was a primary cause of the fibrosis or a consequence of it was unclear. There are few data on the management of pulmonary vein thrombosis, but anticoagulation, antibiotics, and, in cases of large pulmonary vein thrombosis, thrombectomy or pulmonary resection have been used