Diagnostic Accuracy of Clinical Signs and Biochemical Parameters for External Ventricular CSF Catheter-Associated Infection.

Background and Objectives: Few prospective well-designed diagnostic accuracy studies have been performed to study the parameters of infection in patients suspected for external ventricular catheter-associated infection. Our objective was to analyze the diagnostic accuracy of clinical characteristics and biochemical and microbiological parameters in diagnosing external ventricular CSF catheter-associated infection. Methods: From 2014 to 2017, we performed a single-center cohort study in consecutive patients at the intensive care unit who required an external ventricular CSF catheter in the Hague, the Netherlands. CSF was sampled and analyzed daily. Ventricular catheter-associated infection was defined according to the 2017 Infectious Diseases Society of America's Clinical Practice Guidelines. We compared clinical characteristics and biochemical parameters between patients with and without infection from 3 days before to 3 days after the day the CSF sample was collected that grew bacteria. Results: A total of 103 patients were included of whom 15 developed a catheter-associated infection (15%). The median day cultures were positive was 3 days after CSF collection (interquartile range [IQR] +2 to +4). On day 0, none of the tests could differentiate between patients with and without infection. The CSF leukocyte count was increased in patients with ventricular catheter-associated infection as compared with patients without on days +2 and +3. The difference was most prominent on day +2 (1,703 × 106/L [IQR 480-6,296] vs 80 × 106/L [IQR 27-251]; p < 0.001; area under the curve [AUC] 0.87 [95% confidence interval (CI) 0.71-1.00]). Sensitivity for the CSF leukocyte count at a cutoff level >1,000 × 106/L was 67% (95% CI 30-93), and specificity was 100% (95% CI 90-100); the positive predictive value was 100%, and the negative predictive value was 92% (95% CI 83-97). The percentage of polymorphonuclear cells (PMNs) was higher in patients with infection on days +1 and +2 (day +2 89% [IQR 78-94] vs 59% [IQR 39-75]; p < 0.01; AUC 0.91 [95% CI 0.81-1.0]). Discussion: An elevated CSF leukocyte count and increased percentage of PMNs are the strongest indicators for external catheter-associated infections on the days before culture positivity. New CSF markers of drain-associated infection should be studied to enable earlier diagnosis and treatment in patients with an infection and reduce antibiotic treatment in those with no infection. Classification of Evidence: This study provides Class I evidence that in individuals requiring an external ventricular CSF catheter, an elevated CSF leukocyte count and an increased percentage of PMNs are the strongest indicators of catheter-associated infections in the days before CSF culture positivity.

Diagnostic accuracy of four different D-dimer assays: A post-hoc analysis of the YEARS study.

INTRODUCTION: For exclusion of pulmonary embolism (PE) clinical decision rules in combination with a D-dimer assay are applied. Currently available D-dimer assays are not standardized and it is unknown whether these differences have an impact on diagnostic management of suspected PE. Therefore, the aim is to explore differences between D-dimer assays and their impact on diagnostic outcome. METHODS: Data from all patients included in the YEARS study were collected. The YEARS study is a prospective, multicentre, cohort outcome study evaluating 3462 patients with suspected PE in which four different D-dimer assays were applied (Liatest, Innovance, Tinaquant, Vidas). Median D-dimer concentrations were calculated for each D-dimer assay. Sensitivity, specificity, PPV and NPV for detection of PE of all four assays were determined in patients without YEARS items and in those with ≥1 YEARS items (i.e. symptomatic deep vein thrombosis, haemoptysis, and whether PE is the most likely diagnosis). RESULTS: A total of 1323, 1100, 768 and 271 D-dimer concentrations were collected using the Liatest Innovance, Tinaquant and Vidas assay, respectively. Median D-dimer concentrations differed significantly between assays, with lowest values in the Tinaquant assay. In patients without YEARS items using a cutoff level of 1000 ng/mL, the NPV varied from 99,5 to 100%. In patients with ≥1 YEARS items using a 500 ng/mL cutoff, the NPV varied from 97,0 to 100% depending on the assay. CONCLUSIONS: The overall high NPV for all assays demonstrates the clinical value of the D-dimer assay. However, these results confirm differences between D-dimer assays, which have an impact on follow-up imaging. This emphasizes the need for standardization of D-dimer assays.

Procalcitonin in cerebrospinal fluid in meningitis: a prospective diagnostic study.

OBJECTIVES: Bacterial meningitis is a severe but treatable condition. Clinical symptoms may be ambiguous and current diagnostics lack sensitivity and specificity, complicating diagnosis. Procalcitonin (PCT) is a protein that is elevated in serum in bacterial infection. We aimed to assess the value of PCT in cerebrospinal fluid (CSF) in the diagnosis of bacterial meningitis. METHODS: We included patients with bacterial meningitis, both community acquired and post neurosurgery. We included two comparison groups: patients with viral meningitis and patients who underwent lumbar punctures for noninfectious indications. We calculated mean differences and 95% confidence intervals of procalcitonin in CSF and plasma in patients with and without bacterial meningitis. RESULTS: Average PCT concentrations in CSF were 0.60 ng mL-1 (95% CI: 0.29-0.92) in the bacterial meningitis group (n = 26), 0.81 (95% CI: 0.33-1.28) in community-acquired meningitis (n = 16) and 0.28 (95% CI: 0.10-0.45) in postneurosurgical meningitis (n = 10), 0.10 ng mL-1 (95% CI: 0.08-0.12) in the viral meningitis group (n = 14) and 0.08 ng mL-1 (95% CI: 0.06-0.09) in the noninfectious group (n = 14). Mean difference of PCT-CSF between patients with community-acquired bacterial meningitis and with viral meningitis was 0.71 ng mL-1 (95% CI: 0.17-1.25) and 0.73 ng mL-1 (95% CI: 0.19-1.27) for community-acquired bacterial meningitis versus the noninfectious group. The median PCT CSF: plasma ratio was 5.18 in postneurosurgical and 0.18 in community-acquired meningitis (IQR 4.69 vs. 0.28). CONCLUSION: Procalcitonin in CSF was significantly higher in patients with bacterial meningitis when compared with patients with viral or no meningitis. PCT in CSF may be a valuable marker in diagnosing bacterial meningitis, and could become especially useful in patients after neurosurgery.

[Metformin, renal function and lactate: the MetClear Study]. / Metformine, nierfunctie en lactaat: het MetClear-onderzoek.

OBJECTIVE: To map the relation between metformin prescription and renal function in an outpatient setting. To investigate whether there is an association between renal function, metformin concentration and lactate concentration. DESIGN: Pilot for a prospective observational cohort study. METHOD: We included outpatients with diabetes mellitus type 2 who were treated with metformin. At inclusion, we determined the HbA1c, lactate, metformin and creatinine concentrations and the estimated glomerular filtration rate (eGFR). Information on the prescribed dosage of metformin was acquired from patient files. Our primary outcome measure was the number of patients in whom the dose was not adjusted to the renal function. Our secondary outcome measure was the difference in median lactate concentration between patients with a normal (≤ 2.5 mg/l) and an increased (> 2.5 mg/l) metformin concentration. RESULTS: Eighty-eight patients were included, 12 (14%) of whom had an eGFR ≤ 30, 31 (36%) an eGFR of 30-50 and 44 (50%) an eGFR > 51 ml/min/1.73 m2. In 27 (31%) of all patients, the daily dose of metformin exceeded the dose recommended in the practice guidelines. The 28 patients with an increased metformin concentration had a significantly higher median lactate concentration: 2.3 mmol/l compared to 1.5 mmol/l for the 60 patients with a normal metformin concentration (p < 0.0001). CONCLUSION: Our study shows that in outpatient practice, the metformin dose is not sufficiently adjusted to a reduced renal function in 31% of the patients. The accumulation of metformin appears to be associated with an increased lactate concentration and a reduced renal function. Extra attention to the dose of metformin in reduced renal clearance is therefore recommended.

Cost-effectiveness analysis of cardiovascular risk factor screening in women who experienced hypertensive pregnancy disorders at term.

OBJECTIVES: To assess the cost-effectiveness of post-partum screening on cardiovascular risk factors and subsequent treatment in women with a history of gestational hypertension or pre-eclampsia at term. STUDY DESIGN: Two separate Markov models evaluated the cost-effectiveness analysis of hypertension (HT) screening and screening on metabolic syndrome (MetS), respectively, as compared to current practice in women with a history of term hypertensive pregnancy disorders. Analyses were performed from the Dutch health care perspective, using a lifetime horizon. One-way sensitivity analyses and Monte Carlo simulation evaluated the robustness of the results. RESULTS: Both screening on HT and MetS in women with a history of gestational hypertension or pre-eclampsia resulted in increase in life expectancy (HT screening 0.23year (95% CI -0.06 to 0.54); MetS screening 0.14years (95% CI -0.16 to 0.45)). The gain in QALYs was limited, with HT screening and MetS screening generating 0.04 QALYs (95% CI -0.12 to 0.20) and 0.03 QALYs (95% CI -0.14 to 0.19), resulting in costs to gain one QALY of €4228 and €28,148, respectively. Analyses for uncertainty showed a chance of 74% and 75%, respectively, that post-partum screening is cost-effective at a threshold of €60,000/QALY. CONCLUSIONS: According to the available knowledge post-partum screening on cardiovascular risk factors and subsequent treatment in women with a history of gestational hypertension or pre-eclampsia at term is likely to be cost-effective.

Cardiovascular risk factors in women who had hypertensive disorders late in pregnancy: a cohort study.

OBJECTIVE: The purpose of this study was to determine cardiovascular risk factors in women with a history of hypertensive pregnancy disorders at term (HTP) 2.5 years after pregnancy. STUDY DESIGN: In a multicenter cohort study in The Netherlands from June 2008 through November 2010, cardiovascular risk factors were compared between women with a history of HTP (HTP cohort, n = 306) and women with a history of normotensive pregnancies at term (NTP cohort, n = 99). HTP women had participated in a randomized, longitudinal trial assessing the effectiveness of induction of labor in women with hypertensive pregnancy disorders at term. All women were assessed 2.5 years after pregnancy for blood pressure, anthropometrics, glucose, glycosylated hemoglobin, insulin, homeostatic model assessment score, total cholesterol, high-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, and microalbumin and metabolic syndrome. RESULTS: After a mean follow-up period of 2.5 years, hypertension (HTP, 34%; NTP, 1%; P < .001) and metabolic syndrome (HTP, 25%; NTP, 5%; P < .001) were more prevalent in HTP women compared with NTP women. HTP women had significantly higher systolic and diastolic blood pressure, higher body mass index, and higher waist circumference. Glucose, glycosylated hemoglobin, insulin, homeostatic model assessment score, total cholesterol, triglycerides, and high-sensitivity C-reactive protein levels were significantly higher and high-density lipoprotein cholesterol was significantly lower in HTP women. CONCLUSION: In women with a history of HTP, hypertension and metabolic syndrome are more common, and they have higher levels of biochemical cardiovascular risk factors 2.5 years after pregnancy.

Biochemical cardiovascular risk factors after hypertensive pregnancy disorders: a systematic review and meta-analysis.

The objective of this study was to perform a systematic review and meta-analysis of studies assessing biochemical cardiovascular risk factors in women with previous hypertensive pregnancy disorders and women with previous normotensive pregnancies. Data were collected from PubMed and EMBASE (from inception to February 28, 2011) supplemented by manual searches of bibliographies. Included were cohort studies and case-control studies assessing biochemical cardiovascular risk factors in women with previous hypertensive pregnancy disorders compared with women with previous normotensive pregnancies. Of 2573 studies reviewed for eligibility, quality, and data extraction, 22 were included in the review, of which 15 could be meta-analyzed. The pooled mean differences for the outcomes of interest were 0.17 mmol/L (95% confidence interval [CI], 0.08-0.25 mmol/L) for glucose (10 studies), 3.46 mU/mL (95% CI, 2.34-4.58 mU/mL) for insulin (5 studies), 0.13 mmol/L (95% CI, 0.05-0.21) for triglycerides (10 studies), 0.22 mmol/L (95% CI, 0.11-0.33 mmol/L) for total cholesterol (11 studies), -0.11 mmol/L (95% CI, -0.18 to -0.04 mmol/L) for high-density lipoprotein cholesterol (10 studies), and 0.21 mmol/L (95% CI, 0.10-0.32) for low-density lipoprotein cholesterol (9 studies), all in the disadvantage in women with previous hypertensive pregnancy disorders. Analyses for preeclampsia alone showed similar results. CONTINUED LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to assess the long-term cardiovascular consequences after hypertensive pregnancy disorders, evaluate and interpret the evidence regarding biochemical cardiovascular risk factor assessment after pregnancy, and counsel women with a history of hypertensive pregnancy disorders as to the effectiveness of cardiovascular risk factor assessment in the primary prevention of cardiovascular disease. CONCLUSIONS: Women with previous hypertensive pregnancy disorders have higher glucose, insulin, triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels measured after pregnancy compared with women with previous normotensive pregnancies. These biochemical cardiovascular risk factors may identify women who will benefit from primary prevention of cardiovascular disease. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians.

Feasibility of nonselective testing for hemoglobinopathies in early pregnancy in The Netherlands.

OBJECTIVE: To examine the feasibility of standardized hemoglobinopathy (HBP) carrier testing for pregnant women in The Netherlands in addition to the standard anemia screening. METHODS: We assessed the prevalence of HBP in women at the time of the first pregnancy visit using both a prospective cohort (N = 703) and a retrospective series of women selected at random (N = 588). For the purpose of analysis, the population was divided into a high risk and a low risk group for HBP based on maternal ethnicity. Screening for HBP utilized standard screening tests for anemia, with additional high performance liquid chromatography (Variant II); molecular analysis was performed by Gap-polymerase chain reaction (Gap-PCR) and if necessary, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Family history was reported or collected from the medical records. RESULTS: ß-Globin defects were found in 3.9% of the total population (50/1291). The frequency in the high risk population was 5.6% (37/656), compared with 1.2% (6/501) in the low risk group. In the prospective study we found 30 HBP carriers, leading to testing of 16 partners and identification of two couples at risk. One affected child was born. Mean gestational age at the screening was 11.3 weeks with a standard deviation (SD) of 5.8. CONCLUSION: We found that the prevalence of HBP carriers is high enough in our population to warrant HBP testing for the entire multiethnic population in early pregnancy at the time of anemia screening. This is feasible as most women had their booking early in their first trimester.

10-Year cardiovascular event risks for women who experienced hypertensive disorders in late pregnancy: the HyRAS study.

BACKGROUND: Cardiovascular disease is the cause of death in 32% of women in the Netherlands. Prediction of an individual's risk for cardiovascular disease is difficult, in particular in younger women due to low sensitive and specific tests for these women. 10% to 15% of all pregnancies are complicated by hypertensive disorders, the vast majority of which develop only after 36 weeks of gestation. Preeclampsia and cardiovascular disease in later life show both features of "the metabolic syndrome" and atherosclerosis. Hypertensive disorders in pregnancy and cardiovascular disease may develop by common pathophysiologic pathways initiated by similar vascular risk factors. Vascular damage occurring during preeclampsia or gestational hypertension may contribute to the development of future cardiovascular disease, or is already present before pregnancy. At present clinicians do not systematically aim at the possible cardiovascular consequences in later life after a hypertensive pregnancy disorder at term. However, screening for risk factors after preeclampsia or gestational hypertension at term may give insight into an individual's cardiovascular risk profile. METHODS/DESIGN: Women with a history of preeclampsia or gestational hypertension will be invited to participate in a cohort study 2 1/2 years after delivery. Participants will be screened for established modifiable cardiovascular risk indicators. The primary outcome is the 10-year cardiovascular event risk. Secondary outcomes include differences in cardiovascular parameters, SNP's in glucose metabolism, and neonatal outcome. DISCUSSION: This study will provide evidence on the potential health gains of a modifiable cardiovascular risk factor screening program for women whose pregnancy was complicated by hypertension or preeclampsia. The calculation of individual 10-year cardiovascular event risks will allow identification of those women who will benefit from primary prevention by tailored interventions, at a relatively young age. TRIAL REGISTRATION: The HYPITAT trial is registered in the clinical trial register as ISRCTN08132825.

Maternal and paternal thrombophilia: risk factors for perinatal mortality.

BACKGROUND: Although some paternal components to the predisposition to pre-eclampsia have been demonstrated recently, it is not known whether such paternal factors play a role to thrombophilia-related perinatal mortality. OBJECTIVE: To compare the paternal and maternal contribution to perinatal mortality. STUDY DESIGN: Data from a prospective registry of perinatal mortality in a Dutch healthcare region were used. Between December 1999 and May 2000, the prevalence of thrombophilia was studied in 74 women with a history of perinatal mortality (female cases) and 54 of their male partners (male cases). Seventy-one healthy unrelated women after uneventful pregnancies only and 66 of their male partners were used as controls. SETTING: Obstetric outpatient clinic in a regional hospital (Remierde Graaf Group, Deflt). METHODS: Presence of various coagulation abnormalities, hyperhomocysteinaemia and anticardiolipins was investigated. RESULTS: The frequency of antithrombin deficiency (12% vs 0%), increased activated protein C (APC) resistance (32% vs 6%), total protein S deficiency (11% vs 1%) and elevated factor VIII:C activity (43% vs 17%) was significantly higher in female cases compared with controls. In male cases, the frequency of increased APC resistance was significantly higher compared with controls (22% vs 0%). In 30 of the 54 couples with a history of perinatal mortality, more than one thrombophilic abnormality was found (55%) compared with 10 of the 62 control couples (17%). CONCLUSION: The risk of having thrombophilia is doubled in men who have fathered pregnancies which ended in perinatal death as well as in the mothers of such pregnancies.