An evaluation of ciprofloxacin pharmacokinetics in critically ill patients undergoing continuous veno-venous haemodiafiltration

BACKGROUND: The study aimed to investigate the pharmacokinetics of intravenous ciprofloxacin and the adequacy of 400 mg every 12 hours in critically ill Intensive Care Unit (ICU) patients on continuous veno-venous haemodiafiltration (CVVHDF) with particular reference to the effect of achieved flow rates on drug clearance. METHODS: This was an open prospective study conducted in the intensive care unit and research unit of a university teaching hospital. The study population was seven critically ill patients with sepsis requiring CVVHDF.Blood and ultrafiltrate samples were collected and assayed for ciprofloxacin by High Performance Liquid Chromatography (HPLC) to calculate the model independent pharmacokinetic parameters; total body clearance (TBC), half-life (t1/2) and volume of distribution (Vd). CVVHDF was performed at prescribed dialysate rates of 1 or 2 L/hr and ultrafiltration rate of 2 L/hr. The blood flow rate was 200 ml/min, achieved using a Gambro blood pump and Hospal AN69HF haemofilter. RESULTS: Seventeen profiles were obtained. CVVHDF resulted in a median ciprofloxacin t1/2 of 13.8 (range 5.15-39.4) hr, median TBC of 9.90 (range 3.10-13.2) L/hr, a median Vdss of 125 (range 79.5-554) L, a CVVHDF clearance of 2.47+/-0.29 L/hr and a clearance of creatinine (Clcr) of 2.66+/-0.25 L/hr. Thus CVVHDF, at an average flow rate of ~3.5 L/hr, was responsible for removing 26% of ciprofloxacin cleared. At the dose rate of 400 mg every 12 hr, the median estimated Cpmax/MIC and AUC0-24/MIC ratios were 10.3 and 161 respectively (for a MIC of 0.5 mg/L) and exceed the proposed criteria of >10 for Cpmax/MIC and > 100 for AUC0-24/MIC. There was a suggestion towards increased ciprofloxacin clearance by CVVHDF with increasing effluent flow rate. CONCLUSIONS: Given the growing microbial resistance to ciprofloxacin our results suggest that a dose rate of 400 mg every 12 hr, may be necessary to achieve the desired pharmacokinetic - pharmacodynamic (PK-PD) goals in patients on CVVHDF, however an extended interval may be required if there is concomitant hepatic impairment. A correlation between ciprofloxacin clearance due to CVVHDF and creatinine clearance by the filter was observed (r2 = 0.76), providing a useful clinical surrogate marker for ciprofloxacin clearance within the range studied

Prolonged high-dose intravenous magnesium therapy for severe tetanus in the intensive care unit: a case series

<p>Abstract</p> <p>Introduction</p> <p>Tetanus rarely occurs in developed countries, but it can result in fatal complications including respiratory failure due to generalized muscle spasms. Magnesium infusion has been used to treat spasticity in tetanus, and its effectiveness is supported by several case reports and a recent randomized controlled trial.</p> <p>Case presentations</p> <p>Three Caucasian Greek men aged 30, 50 and 77 years old were diagnosed with tetanus and admitted to a general 12-bed intensive care unit in 2006 and 2007 for respiratory failure due to generalized spasticity. Intensive care unit treatment included antibiotics, hydration, enteral nutrition, early tracheostomy and mechanical ventilation. Intravenous magnesium therapy controlled spasticity without the need for additional muscle relaxants. Their medications were continued for up to 26 days, and adjusted as needed to control spasticity. Plasma magnesium levels, which were measured twice a day, remained in the 3 to 4.5 mmol/L range. We did not observe hemodynamic instability, arrhythmias or other complications related to magnesium therapy in these patients. All patients improved, came off mechanical ventilation, and were discharged from the intensive care unit in a stable condition.</p> <p>Conclusion</p> <p>In comparison with previous reports, our case series contributes the following meaningful additional information: intravenous magnesium therapy was used on patients already requiring mechanical ventilation and remained effective for up to 26 days (significantly longer than in previous reports) without significant toxicity in two patients. The overall outcome was good in all our patients. However, the optimal dose, optimal duration and maximum safe duration of intravenous magnesium therapy are unknown. Therefore, until more data on the safety and efficacy of magnesium therapy are available, its use should be limited to carefully selected tetanus cases.</p

Cognitive impairment in patients with Fibromyalgia syndrome as assessed by the Mini-Mental State Examination

<p>Abstract</p> <p>Background</p> <p>This study evaluated the frequency of cognitive impairment in patients with Fibromyalgia syndrome (FMS) using the Mini Mental State Examination (MMSE).</p> <p>Methods</p> <p>We analyzed baseline data from all 46 patients with FMS and 92 age- and sex-matched controls per diagnosis of neuropathic (NeP) or mixed pain (MP) selected from a larger prospective study.</p> <p>Results</p> <p>FMS had a slight but statistically significant lower score in the adjusted MMSE score (26.9; 95% CI 26.7-27.1) than either NeP (27.3; 95% CI 27.2-27.4) or MP (27.3; 27.2-27.5). The percentage of patients with congnitive impairment (adjusted MMSE ≤ 26) was numerically higher in FMS (15%; 95% CI 6.3-29) compared with NeP (5%; 95% CI 1.8-12.2) or MP (5%; 95% CI 1.8-12.2) and higher than in the same age stratum of the general population (0.05%).</p> <p>Conclusions</p> <p>Compared with the population reference value, patients with FMS showed high frequency of cognitive impairment.</p

Is relatively young age within a school year a risk factor for mental health problems and poor school performance? A population-based cross-sectional study of adolescents in Oslo, Norway

BACKGROUND: Several studies have shown that children who are relatively young within a school year are at greater risk for poorer school performance compared with their older peers. One study also reported that relative age within a school year is an independent risk factor for emotional and behavioral problems. The objective of this study was to test the hypothesis that relatively younger adolescents in the multiethnic population of Oslo have poorer school performance and more mental health problems than their relatively older classmates within the same school year. METHODS: This population-based cross-sectional study included all 10(th)-grade pupils enrolled in 2000 and 2001 in the city of Oslo. The participation rate was 88%. Of the 6,752 pupils in the study sample, 25% had a non-Norwegian background. Mental health problems were quantified using the abbreviated versions of Symptom Check List-25 (SCL-10) and the Strength and Difficulties Questionnaire (SDQ). Information on school performances and mental health problems were self-reported. We controlled for confounding factors including parental educational level, social support, gender, and ethnicity. RESULTS: The youngest one-third of pupils had significantly lower average school grades than the middle one-third and oldest one-third of their classmates (p < 0.001). Of the mental health problems identified in the questionnaires, the groups differed only on peer problems; the youngest one-third reported significantly more problems than the middle and oldest groups (p < 0.05). Age within a school year and gender showed significant interactions with total SDQ score, SDQ peer problems score, SDQ pro social score, and SCL-10 score. After stratifying for gender, the peer problem scores differed significantly between age groups only among boys. The SCL-10 score was significant, but only in girls and in the opposite direction to that expected, with the oldest pupils having significantly higher scores than the other two groups (p < 0.05). CONCLUSION: In adolescents from a multicultural city in Norway, relative age within a school year significantly influenced academic performance. In contrast to data from Great Britain, relative age within a school year was not an important risk factor for mental health problems in adolescents in Oslo

The mental health of populations directly and indirectly exposed to violent conflict in Indonesia

Background Large disasters affect people who live both near and far from the areas in which they occur. The mental health impact is expected to be similar to a ripple effect, where the risk of mental health consequences generally decreases with increasing distance from the disaster center. However, we have not been able to identify studies of the ripple effect of man-made disaster on mental health in low-income countries. Objectives The objective was to examine the hypothesis of a ripple effect on the mental health consequences in populations exposed to man-made disasters in a developing country context, through a comparison of two different populations living in different proximities from the center of disaster in Mollucas. Methods Cross-sectional longitudinal data were collected from 510 Internally Displaced Persons (IDPs) living in Ambon, who were directly exposed to the violence, and non-IDPs living in remote villages in Mollucas, Indonesia, who had never been directly exposed to violence in Mollucas. Data were collected during home visits and statistical comparisons were conducted by using chi square tests, t-test and logistic regression. Results There was significantly more psychological distress "caseness" in IDPs than non-IDPs. The mental health consequences of the violent conflict in Ambon supported the ripple effect hypothesis as displacement status appears to be a strong risk factor for distress, both as a main effect and interaction effect. Significantly higher percentages of IDPs experienced traumatic events than non-IDPs in all six event types reported. Conclusions This study indicates that the conflict had an impact on mental health and economic conditions far beyond the area where the actual violent events took place, in a diminishing pattern in line with the hypothesis of a ripple effect

Response rates and selection problems, with emphasis on mental health variables and DNA sampling, in large population-based, cross-sectional and longitudinal studies of adolescents in Norway

Background Selection bias is a threat to the internal validity of epidemiological studies. In light of a growing number of studies which aim to provide DNA, as well as a considerable number of invitees who declined to participate, we discuss response rates, predictors of lost to follow-up and failure to provide DNA, and the presence of possible selection bias, based on five samples of adolescents. Methods We included nearly 7,000 adolescents from two longitudinal studies of 18/19 year olds with two corresponding cross-sectional baseline studies at age 15/16 (10th graders), and one cross-sectional study of 13th graders (18/19 years old). DNA was sampled from the cheek mucosa of 18/19 year olds. Predictors of lost to follow-up and failure to provide DNA were studied by Poisson regression. Selection bias in the follow-up at age 18/19 was estimated through investigation of prevalence ratios (PRs) between selected exposures (physical activity, smoking) and outcome variables (general health, mental distress, externalizing problems) measured at baseline. Results Out of 5,750 who participated at age 15/16, we lost 42% at follow-up at age 18/19. The percentage of participants who gave their consent to DNA provision was as high as the percentage that consented to a linkage of data with other health registers and surveys, approximately 90%. Significant predictors of lost to follow-up and failure to provide DNA samples in the present genetic epidemiological study were: male gender; non-western ethnicity; postal survey compared with school-based; low educational plans; low education and income of father; low perceived family economy; unmarried parents; poor self-reported health; externalized symptoms and smoking, with some differences in subgroups of ethnicity and gender. The association measures (PRs) were quite similar among participants and all invitees, with some minor discrepancies in subgroups of non-western boys and girls. Conclusions Lost to follow-up had marginal impact on the estimated prevalence ratios. It is not likely that the invitation to provide DNA influenced the response rates of 18/19 year olds. Non-western ethnicity, male gender and characteristics related to a low social class and general and mental health problems measured at baseline are associated with lost to follow-up and failure to provide DNA

Incorporating clinical guidelines through clinician decision-making

<p>Abstract</p> <p>Background</p> <p>It is generally acknowledged that a disparity between knowledge and its implementation is adversely affecting quality of care. An example commonly cited is the failure of clinicians to follow clinical guidelines. A guiding assumption of this view is that adherence should be gauged by a standard of conformance. At least some guideline developers dispute this assumption and claim that their efforts are intended to inform and assist clinical practice, not to function as standards of performance. However, their ability to assist and inform will remain limited until an alternative to the conformance criterion is proposed that gauges how evidence-based guidelines are incorporated into clinical decisions.</p> <p>Methods</p> <p>The proposed investigation has two specific aims to identify the processes that affect decisions about incorporating clinical guidelines, and then to develop ad test a strategy that promotes the utilization of evidence-based practices. This paper focuses on the first aim. It presents the rationale, introduces the clinical paradigm of treatment-resistant schizophrenia, and discusses an exemplar of clinician non-conformance to a clinical guideline. A modification of the original study is proposed that targets psychiatric trainees and draws on a cognitively rich theory of decision-making to formulate hypotheses about how the guideline is incorporated into treatment decisions. Twenty volunteer subjects recruited from an accredited psychiatry training program will respond to sixty-four vignettes that represent a fully crossed 2 × 2 × 2 × 4 within-subjects design. The variables consist of criteria contained in the clinical guideline and other relevant factors. Subjects will also respond to a subset of eight vignettes that assesses their overall impression of the guideline. Generalization estimating equation models will be used to test the study's principal hypothesis and perform secondary analyses.</p> <p>Implications</p> <p>The original design of phase two of the proposed investigation will be changed in recognition of newly published literature on the relative effectiveness of treatments for schizophrenia. It is suggested that this literature supports the notion that guidelines serve a valuable function as decision tools, and substantiates the importance of decision-making as the means by which general principles are incorporated into clinical practice.</p

Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study.

BACKGROUND: Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions. METHODS: We developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal-external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London). FINDINGS: 74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal-external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [-0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model. INTERPRETATION: The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19. FUNDING: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London

Understanding the complexity of glycaemic health: systematic bio-psychosocial modelling of fasting glucose in middle-age adults; a DynaHEALTH study

© The Author(s) 2018. Background: The prevention of the risk of type 2 diabetes (T2D) is complicated by multidimensional interplays between biological and psychosocial factors acting at the individual level. To address the challenge we took a systematic approach, to explore the bio-psychosocial predictors of blood glucose in mid-age. Methods: Based on the 31-year and 46-year follow-ups (5,078 participants, 43% male) of Northern Finland Birth Cohort 1966, we used a systematic strategy to select bio-psychosocial variables at 31 years to enable a data-driven approach. As selection criteria, the variable must be (i) a component of the metabolic syndrome or an indicator of psychosocial health using WHO guidelines, (ii) easily obtainable in general health check-ups and (iii) associated with fasting blood glucose at 46 years (P < 0.10). Exploratory and confirmatory factor analysis were used to derive latent factors, and stepwise linear regression allowed exploration of relationships between factors and fasting glucose. Results: Of all 26 variables originally considered, 19 met the selection criteria and were included in an exploratory factor analysis. Two variables were further excluded due to low loading (<0.3). We derived four latent factors, which we named as socioeconomic, metabolic, psychosocial and blood pressure status. The combination of metabolic and psychosocial factors, adjusted for sex, provided best prediction of fasting glucose at 46 years (explaining 10.7% of variation in glucose; P < 0.001). Regarding different bio-psychosocial pathways and relationships, the importance of psychosocial factors in addition to established metabolic risk factors was highlighted. Conclusions: The present study supports evidence for the bio-psychosocial nature of adult glycemic health and exemplifies an evidence-based approach to model the bio-psychosocial relationships. The factorial model may help further research and public health practice in focusing also on psychosocial aspects in maintaining normoglycaemia in the prevention of cardio-metabolic diseases.European Union’s Horizon 2020 research and innovation programme, grant agreement No 633595