Inflammatory response and optimalisation of perioperative fluid administration during hyperthermic intraoperative intraperitoneal chemotherapy surgery.

BACKGROUND: Surgical cytoreduction and simultaneous hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis has a high incidence of postoperative complications. Inadequate intraoperative volume therapy is a known risk factor for the development of postoperative complications. Another possible risk factor is the inflammatory response due to surgery and HIPEC. The aim of this observational pilot study was to monitor fluid intake in the first 24 hours peri- and postoperative by using a non-invasive cardiac output indicator. Furthermore, we measured circulating cytokines and evaluated the possible relation of these changes of inflammatory response with the non-invasive monitored fluid management. METHODS: Twenty-four patients undergoing cytoreductive surgery and HIPEC for peritoneal carcinomatosis were included. Patients were randomised into either a liberal fluid management group using intra-arterial blood pressure and central venous pressure measurement or a restrictive group by using intra-arterial blood pressure and central venous pressure measurement with FloTrac/Vigileo monitoring. Cytokines were measured with multiplex immunoassays. RESULTS: We found no difference in the amount of fluid administration in patients undergoing HIPEC surgery with FloTrac/Vigileo monitoring compared to standard care. Furthermore, there was no difference in mortality, ICU and hospital length of stay between both groups. A severe inflammatory response was seen in all patients after the HIPEC procedure with a rapid increase of interleukins and C-reactive protein (CRP). There was however no difference between our intervention and control group in the severity of this reaction. Finally, we found no relation between the severity of the inflammatory response and mortality, or a composite end-point of mortality and severe complications within 30 days postoperative. CONCLUSIONS: FloTrac/Vigileo monitoring does not lead to a more restrictive fluid administration and does not influence short-term clinical course in patients undergoing HIPEC surgery. The procedure itself leads to a severe inflammatory response, which is not affected by the use of FloTrac/Vigileo. Our data do not support the use of FloTrac/Vigileo monitoring in patients undergoing HIPEC surgery concerning fluid restrictive management.

Aortic disease in patients with Marfan syndrome: aortic volume assessment for surveillance.

PURPOSE: To assess the reproducibility of aortic volume estimates and to serially test their use in patients with Marfan syndrome. MATERIALS AND METHODS: The study was approved by the medical ethics committee and all subjects gave written informed consent. In 81 patients with Marfan syndrome and seven healthy control subjects, aortic volumes and diameters at baseline were estimated by means of contrast material-enhanced magnetic resonance (MR) imaging. At 3 years of follow-up, aortic expansion rate were calculated in a subgroup of 22 patients with Marfan syndrome. Total aortic volume was defined as volume measurement from the level of the aortic annulus to the aortic bifurcation. Intra- and interobserver agreement of aortic volume were calculated by using the intraclass correlation coefficient. Differences in variables were analyzed with the Student t test and logistic regression. Effect size was calculated. RESULTS: Intra- and interobserver agreement of aortic volume calculation was 0.996 and 0.980, respectively. Mean aortic volume was significantly greater in patients with Marfan syndrome than in control subjects (104 mL/m(2); 95% confidence interval [CI]: 95, 114 mL/m(2) vs 74 mL/m(2); 95% CI: 62, 87 mL/m(2); P < .001). In 22 patients with Marfan syndrome, mean aortic volume was increased at 3 years of follow-up (17 mL; 95% CI: 8, 26 mL; P = .001; effect size, 0.29), while mean aortic diameter did not increase significantly (0.4 mm; 95% CI: 0.0, 0.9 mm; P = .171; effect size, 0.13). CONCLUSION: Assessment of aortic volume is highly reproducible and may be suited for use in the detection of aortic expansion in patients with Marfan syndrome. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122310/-/DC1.

Mental quality of life is related to a cytokine genetic pathway.

BACKGROUND: Quality of life (QoL) in patients with chronic disease is impaired and cannot be solely explained by disease severity. We explored whether genetic variability and activity contributes to QoL in patients with Marfan syndrome (MFS), a genetic connective tissue disorder. METHODOLOGY/PRINCIPAL FINDINGS: In 121 MFS patients, patient characteristics (i.e. demographics and MFS-related symptoms) were assessed. Patients completed the SF-36 to measure QoL. In addition, transcriptome wide gene expression and 484 Single Nucleotide Polymorphysms (SNPs) in cytokine genes were available. QoL was first analyzed and associated with patient characteristics. Patients' physical QoL was impaired and weakly related with age and scoliosis, whereas mental quality of life (MCS) was normal. To explain a largely lacking correlation between disease severity and QoL, we related genome wide gene expression to QoL. Patients with lower MCS scores had high expression levels of CXCL9 and CXCL11 cytokine-related genes (p=0.001; p=0.002); similarly, patients with low vitality scores had high expression levels of CXCL9, CXCL11 and IFNA6 cytokine-related genes (p=0.02; p=0.02; p=0.04), independent of patient characteristics. Subsequently, we associated cytokine related SNPs to mental QoL (MCS and vitality). SNP-cluster in the IL4R gene showed a weak association with MCS and vitality (strongest association p=0.0017). Although overall mental QoL was normal, >10% of patients had low scores for MCS and vitality. Post-hoc analysis of systemic inflammatory mediators showed that patients with lowest MCS and vitality scores had high levels of CCL11 cytokine (p=0.03; p=0.04). CONCLUSIONS/SIGNIFICANCE: Variation in the cytokine genetic pathway and its activation is related to mental QoL. These findings might allow us to identify and, ultimately, treat patients susceptible to poor QoL.

Inflammation aggravates disease severity in Marfan syndrome patients.

BACKGROUND: Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-ß signaling. However, the contribution of tissue inflammation is not addressed so far. METHODOLOGY/PRINCIPAL FINDINGS: Here we showed that both TGF-ß and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-ß and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-ß were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients. CONCLUSION/SIGNIFICANCE: In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.

Intrinsic biventricular dysfunction in Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is an autosomal, dominantly inherited, connective tissue disorder usually caused by a mutation in the fibrillin-1 gene (FBN1). As fibrillin-1 is a component of the extracellular matrix of the myocardium, mutations in FBN1 may cause impairment of ventricular function. Furthermore, aortic elasticity is decreased in patients with MFS, which might also impair ventricular function. We assessed biventricular function and the influence of aortic elasticity in patients with MFS by means of cardiac MRI. METHODS AND RESULTS: Cardiac magnetic resonance was performed in 144 patients with MFS without significant valvular dysfunction, previous cardiac surgery or previous aortic surgery. Biventricular diastolic and systolic volumes were measured, and ejection fractions were calculated. Flow wave velocity, a measurable derivative of aortic elasticity, was measured between the ascending aorta and the bifurcation. When compared to healthy controls (n = 19), left ventricular ejection fraction (LVEF) was impaired in patients with MFS (53% ± 7% vs 57% ± 4%, p < 0.005), as was right ventricular ejection fraction (RVEF) (51% ± 7% vs 56% ± 4%, p < 0.005). LVEF and RVEF were strongly correlated. (r = 0.7, p < 0.001). No significant differences were found between patients with ß-blocker treatment and those without. There was no correlation between aortic elasticity as measured by flow wave velocity and LVEF. CONCLUSIONS: Biventricular ejection fraction was impaired in patients with MFS, and the impairment was independent of aortic elasticity and ß-blocker usage. There was also a strong correlation between LVEF and RVEF. Our findings suggest intrinsic myocardial dysfunction in patients with MFS. Clinical trial registration http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 1423. Unique Identifier: NTR1423.

Sexuality in adult patients with congenital heart disease and their partners.

Data on relational and sexuality issues in adult patients with congenital heart disease (CHD) are scarce. The present study aimed to evaluate relational and sexual behaviors, satisfaction, and functioning in a representative sample of patients with CHD and their partners. In addition, we aimed to evaluate the relation between sexuality parameters and quality of life. Relational and sexuality issues were assessed using a sexuality questionnaire in 133 patients (52% men, 37 ± 13 years old) with CHD (43 with coarctation of the aorta, 42 with transposition of great arteries, 36 with Marfan syndrome, and 12 with Eisenmenger syndrome), and 74 partners. Quality of life was assessed using the Dutch translation of the Medical Outcomes Study Short Form 36-Item Health Survey. Data were compared to an age- and gender-matched control group (n = 3,642). Seventy-one percent of patients with CHD were involved in a relationship, which was significantly less compared to controls (79%, p < 0.05). Nonetheless, patients perceived their relationship as more satisfactory compared to controls (p < 0.05). Overall, sexual satisfaction was equal in patients compared to controls, although they perceived lower body esteem (p < 0.001), decreased sexual esteem (p < 0.05), and more distress during sex (p < 0.001). Patients reported no more erectile and lubrication problems compared to partners and to controls. We found significant associations between most relational and sexual parameters and quality of life. In conclusion, many aspects of sexuality are affected in adult patients with CHD, whereas their partners remain relatively unaffected. Moreover, sexuality is an important aspect of quality of life in these patients. We advise physicians to be receptive to discuss sexuality issues and provide patients with adequate therapy.

Losartan therapy in adults with Marfan syndrome: study protocol of the multi-center randomized controlled COMPARE trial.

BACKGROUND: Marfan syndrome (MFS) is one of the most common systemic disorders of connective tissue with the incidence of approximately 2-3 per 10 000 individuals. Aortic disease, leading to progressive aneurysmal dilatation and dissection is the main cause of morbidity and mortality of Marfan patients. Current treatment (e.g. beta blockers and elective surgery) does postpone but cannot prevent aortic complications in these patients. Recent studies have found transforming growth factor beta (TGF beta) to be involved in the aortic aneurysm formation. Losartan, an angiotensin II type 1 receptor blocker inhibits TGFbeta in a mouse model of Marfan syndrome leading to inhibition of aortic growth. The main objective of this trial is to assess whether losartan treatment leads to a clinically relevant decrease of aortic dilatation in adult patients with Marfan syndrome. METHODS/DESIGN: COMPARE study (COzaar in Marfan Patients Reduces aortic Enlargement) is an open-label, randomized, controlled trial with blinded end-points. Treatment with losartan will be compared with no additional treatment after 3 years of follow-up. We will enroll 330 patients with MFS who will be randomly assigned to receive losartan or not. Patients taking beta-blockers will continue taking their standard treatment. The primary end-point is the largest change in aortic diameter at any aortic level measured by means of MRI. Secondary end-points are change in mortality, incidence of dissection, elective aortic surgery, aortic volume, aortic stiffness and ventricular function. We will also investigate gene and protein expression change in the skin under losartan therapy and create prediction models for losartan-treatment response and aortic dilatation. DISCUSSION: The COMPARE study will provide important evidence of effects of losartan treatment in adult Marfan patient population. We expect losartan to significantly reduce the occurrence and progression of aortic dilatation. This trial investigates a wide spectrum of clinical, genetic and biochemical effects of losartan aiming to provide further insight in the pathogenesis and treatment of Marfan syndrome. TRIAL REGISTRATION: Netherlands Trial Register NTR1423.

Automated detection of malaria pigment: feasibility for malaria diagnosing in an area with seasonal malaria in northern Namibia.

OBJECTIVE: To evaluate the feasibility of automated malaria detection with the Cell-Dyn 3700 (Abbott Diagnostics, Santa Clara, CA, USA) haematology analyser for diagnosing malaria in northern Namibia. METHODS: From April to June 2003, all patients with a positive blood smear result and a subset of patients with no suspicion of malaria were included. Blood smear and a venous blood sample (to determine haemoglobin, platelet and malaria pigment levels) were collected from each patient. Malaria pigment test characteristics, correlations with blood parameters and pigment clearance time were calculated. Finally, a subset of blood samples was run twice to evaluate the consistency of test outcome. RESULTS: Two hundred and eight patients were included. Ninety had a positive blood smear result of which 84 tested positive for malaria pigment and 118 patients had a negative blood smear result of which four tested positive for malaria pigment. Test characteristics as compared with microscopy were as follows: sensitivity 0.93, specificity 0.97, positive predictive value 0.95, negative predictive value 0.95. Rerun of the blood samples resulted in a change of diagnosis in 14%. After 4 weeks, 33% of patients with an initially positive pigment result still tested positive. Malaria pigment was found to be negatively correlated with haemoglobin. CONCLUSIONS: Automated detection of malaria pigment is a useful diagnostic tool in this semi-rural area. In low-risk malaria season, the test can be used for diagnosing malaria because of the high sensitivity. In high-risk malaria season, the test can be used for excluding malaria in case of a negative pigment result because of the high specificity.