University Hospital Groningen Research Articles

Darunavir Population Pharmacokinetic Model Based on HIV Outpatient Data.

Darunavir is a second-generation protease inhibitor and is registered for the treatment of HIV-1 infection. The aim of this study was to develop and validate a darunavir population pharmacokinetic model based on data from daily practice. Data sets were obtained from 2 hospitals: ASST Fatebenefratelli Sacco University Hospital, Italy (hospital A), and University Medical Center Groningen, the Netherlands (hospital B). A pharmacokinetic model was developed using data from the largest data set using the iterative two-stage Bayesian procedure within the MWPharm software package. External validation was conducted using data from the smaller data set with Passing-Bablok regression and Bland-Altman analyses. In total, data from 198 patients from hospital A and 170 patients from hospital B were eligible for inclusion. A 1-compartment model with first-order absorption and elimination resulted in the best model. The Passing-Bablok analysis demonstrated a linear correlation between measured concentration and predicted concentration with r = 0.97 (P < 0.05). The predicted values correlated well with the measured values as determined by a Bland-Altman analysis and were overestimated by a mean value of 0.12 mg/L (range 0.23-0.94 mg/L). A total of 98.2% of the predicted values were within the limits of agreement. A robust population pharmacokinetic model was developed, which can support therapeutic drug monitoring of darunavir in daily outpatient settings.

Validation of the Distress Thermometer and Problem List in Patients with Recurrent Respiratory Papillomatosis.

Objective There is no specific clinical tool for physicians to detect psychosocial and physical distress or health care need in patients with recurrent respiratory papillomatosis (RRP). The main aim of this study is to validate the RRP-adapted Distress Thermometer and Problem List (DT&PL). Study Design Prospective cross-sectional questionnaire research. Setting Academic tertiary care medical centers in Groningen, Netherlands, and Helsinki, Finland. Subjects and Methods Ninety-one juvenile- and adult-onset RRP patients participated from the departments of otorhinolaryngology-head and neck surgery of the University Medical Center Groningen, Netherlands, and Helsinki University Hospital, Finland. The Hospital Anxiety and Depression Scale was used as the gold standard. Results A DT cutoff score ≥4 gave the best sensitivity and specificity. Thirty-one percent of patients had significant distress according to the DT cutoff. Significantly more patients with a score above than under the cutoff had a referral wish. The PL appeared to be reliable. Patients' opinions on the DT&PL were largely favorable. Conclusion The Dutch and Finnish versions of the DT&PL are valid, reliable screening tools for distress in RRP patients.

Size matching in lung transplantation: An evidence-based review

The evidence base for size matching between donors and recipients in lung transplantation has not recently been reviewed in a comprehensive manner. Our aim in this study was to assimilate published studies that have addressed size matching of donors to recipients and to establish a pragmatic understanding of the range of lung sizes that may be used for lung transplantation. A comprehensive literature search was performed using Medline and PubMed up to and including September 2012, to identify scientific articles that relate to size matching between donors and lung transplant recipients. Seventy-two articles were identified, of which 21 had addressed the question of the impact of size mismatching on outcomes in lung transplantation. No study has specifically tested the consequences of intentionally mismatching above or below the hypothetical limits for double lung transplantation of a predicted total lung capacity for the donor of between 75% and 125% of the recipient predicted total lung capacity as set out in the ISHLT consensus report on lung donor acceptability criteria. Research is lacking that has robustly defined limits for size mismatch for single lung transplantation and for recipients with restrictive lung pathologies such as pulmonary fibrosis. Published research on the impact of size mismatching between lung transplant donors and recipients is limited by study design and size. It is centered on addressing the issue of mismatch in double lung transplantation in cohorts with a diagnostically heterogeneous make-up and in single lung transplant patients with chronic obstructive pulmonary disease.

Experienced stigmatization reduced quality of life of patients with a neuromuscular disease: a cross-sectional study

Objective: To examine the influence of stigma on the quality of life of patients with a neuromuscular disease. Design: Cross-sectional postal survey. Setting: Outpatient clinic of the Department of Neurology, University Hospital Groningen, the Netherlands. Subjects: Patients diagnosed with a neuromuscular disease. Measures: The Stigma Scale for Chronic Illness, the World Health Organization Quality of Life – abbreviated version questionnaires and some background and disease-related questions. The Stigma Scale for Chronic Illness was translated into Dutch according to international guidelines. The impact of stigma on quality of life was estimated using hierarchical multiple regression analysis after controlling for the extent of limitations and patient characteristics. Results: In total 235 patients (75% response rate) were diagnosed with neuromuscular disease and represented all four categories of the approximately 600 neuromuscular diseases. Most patients (86%) reported self stigma, while 64% reported to experience enacted stigma. Experienced quality of life was moderate to good. Stigma contributed to a unique and substantial extent to all domains of quality of life: explained variance for the impact of stigma on quality ranged from 0.13 (social relations) to 0.34 (physical functioning) for self stigma and from 0.09 (social relations) to 0.11 (physical and psychological health, and quality of the environment). Conclusion: Self stigma was a stronger predictor for poorer quality of life compared with enacted stigma. In other words: patients suffered more from shame and fear for discrimination (self stigma) than from the really experienced discrimination and exclusion (enacted stigma).

Minor neurological dysfunction in children with autism spectrum disorder

The aim of this study was to improve the understanding of brain function in children with autism spectrum disorder (ASD) in relation to minor neurological dysfunctions (MNDs). We studied MNDs in 122 children (93 males, 29 females; mean age 8 y 1 mo, SD 2 y 6 mo) who, among a total cohort of 705 children (513 males, 192 females; mean age 9 y, SD 2 y 0.5 mo) referred to a regional outpatient non-academic psychiatric centre in the Netherlands, were diagnosed with ASD after an extensive multidisciplinary psychiatric assessment. Children with clear neurological abnormalities (e.g. cerebral palsy or spina bifida) were excluded from the study. MNDs were assessed in all 705 children using the Touwen examination method. Special attention was paid to the severity and type of MND. Data of the children with ASD were compared with neurological morbidity data of children with other psychiatric disorders and with children in the general population, who were born at Groningen University Hospital between 1975 and 1978. Seventy-four percent of the children with ASD showed complex MNDs compared with 52% of the children with other psychiatric disorders and 6% of the reference group (χ(2) =18.0, p<0.001; χ(2) =937.5, p<0.001 respectively). Specific dysfunctions frequently encountered in ASD were dysfunctional posture and muscle tone, fine manipulative disability, dyscoordination, and excessive associated movements. These findings suggest a contribution of dysfunctional supraspinal networks involving multiple parts of the brain in the pathogenesis of ASD. This is consistent with findings from neuroimaging studies, and highlights the importance of neurological examinations in paediatric psychiatric assessments.

Side Effects of Oral Dexamethasone Pulse Therapy for Idiopathic Sudden Sensorineural Hearing Loss

To the Editor: In reaction to clinical practice article by Steven D. Rauch (1) in the August 21 issue of the New England Journal on sudden deafness and the following correspondence in Otology Neurotology on intratympanic treatment of this disease, we would like to comment on the use of a dexamethasone 3-day pulse therapy as studied by Westerlaken et al. (2) in comparison to a 7-day prednisolone taper in a double-blind, randomized, controlled trial as mentioned on page 836 by Rauch (1). Rauch comments rightly on the possible severe side effects of corticosteroid treatment, including elevated blood sugar levels, elevated blood pressure, mood change, sleep disturbances, flushing, gastritis, and weight gain. As we implemented the 3-day dexamethasone pulse therapy treatment in our hospital after the study by Westerlaken, a former colleague of ours, we would like to stress the importance of utter care in following the exclusion criteria, like diabetes mellitus, cardiac history, hypertension, pregnancy, stomach ulcer, renal failure, use of oral anticoagulant or corticosteroids, and Cushing syndrome. We have experienced patients with raising blood pressures, mood disturbances, sleep disturbances, and flushes and observed that this seems to be more often the case in the 3-day dexamethasone treatment than in the prednisolone taper therapy. Also, 1 patient treated with the 3-day dexamethasone course developed a myocardial infarction while his previously existing diabetes mellitus derailed, without regaining the lost hearing. Obviously, that is too high a price to be paid, especially for a disease from which 45 to 65% show spontaneous improvement (3,4). Perhaps because of his preexisting (well-regulated) diabetes mellitus, our patient should not have started the treatment in the first place; however, only badly regulated insulin-dependent diabetes mellitus is one of our exclusion criteria for this type of treatment. We would like to urge physicians to take the severe risks of oral dexamethasone pulse therapy and prednisolone taper therapy seriously and refrain from prescribing this treatment to the group of patients known with exclusion criteria as previously mentioned. A hopeful but expensive alternative could be the intratympanic corticosteroid treatments that are currently being studied and discussed (5,6). However, also doing nothing might be an interesting type of treatment, although difficult for physicians; as the Cochrane Review of Wei pointed out, the efficacy of corticosteroid therapy for sudden sensorineural hearing loss remains unproven (3). Rolien H. Free, M.D., Ph.D.* Noor D. Smale, M.D.* Emile de Kleine, Ph.D.† Bernard F. A. M. van der Laan, M.D., Ph.D.* *Department of Otorhinolaryngology-Head and Neck Surgery and †University Audiological Center Groningen University Hospital Groningen The Netherlands

Up-regulation and Cytoprotective Role of Epithelial Multidrug Resistance-associated Protein 1 in Inflammatory Bowel Disease

MRP1 (multidrug resistance-associated protein 1) is well known for its role in providing multidrug resistance to cancer cells. In addition, MRP1 has been associated with both pro- and anti-inflammatory functions in nonmalignant cells. The pro-inflammatory function is evident from the fact that MRP1 is a high affinity transporter for cysteinyl-leukotriene C4 (LTC4), a lipid mediator of inflammation. It remains unexplained, however, why the absence of Mrp1 leads to increased intestinal epithelial damage in mice treated with dextran-sodium sulfate, a model for inflammatory bowel disease (IBD). We found that MRP1 expression is induced in the inflamed intestine of IBD patients, e.g. Crohn disease and ulcerative colitis. Increased MRP1 expression was detected at the basolateral membrane of intestinal epithelial cells. To study a putative role for MRP1 in protecting epithelial cells against inflammatory cues, we manipulated MRP1 levels in human epithelial DLD-1 cells and exposed these cells to cytokines and anti-Fas. Inhibition of MRP1 (by MK571 or RNA interference) resulted in increased cytokine- and anti-Fas-induced apoptosis of DLD-1 cells. Opposite effects, e.g. protection of DLD-1 cells against cytokine- and anti-Fas-induced apoptosis, were observed after recombinant MRP1 overexpression. Inhibition of LTC4 synthesis reduced anti-Fas-induced apoptosis when MRP1 function was blocked, suggesting that LTC4 is the pro-apoptotic compound exported by epithelial MRP1 during inflammation. These data show that MRP1 protects intestinal epithelial cells against inflammation-induced apoptotic cell death and provides a functional role for MRP1 in the inflamed intestinal epithelium of IBD patients.

The Dutch translation of the Childhood Health Assessment Questionnaire: an explorative study of the ceiling effect

Address: 1Department of Pediatric Physical Therapy & Paediatric Exercise Physiology, Het Wilhelmina Kinderziekenhuis, University Children's Hospital, Utrecht, Utrecht, Netherlands, 2Department of Pediatric Physiotherapy, Sophia Children's Hospital, Erasmus University, Rotterdam, Zuid-Holland, Netherlands, 3Department of Physiotherapy (HO-Q), Leiden University Medical Centre, Leiden, Zuid-Holland, Netherlands, 4Department Physiotherapy, University Hospital Groningen, Groningen, Groningen, Netherlands and 5Department Paediatric Physiotherapy, University Medical Center Nijmegen St. Radboud, Nijmegen, Gelderland, Netherlands * Corresponding author

Stigma: The Stealth Weapon of the NTD

Stigma: The Stealth Weapon of the NTD

Accuracy of propofol TOI in combination with sufentanil

1Department of Anesthesiology and Intensive care medicine, University of Bonn, Germany; 2Department of Anesthesiology, Groningen University Hospital, The Netherlands

Evidence‐based treatment and quality of life in heart failure

To explore whether prescription of evidence-based drug therapy is associated with better quality of life (QoL) in patients with heart failure (HF). Patients (n = 62) were recruited in the outpatient clinic of Groningen University Hospital. Inclusion criteria were previous diagnosis of HF, age 40-80 years; ejection fraction of less than 45%, free from other serious disease (such as cancer) and psychiatric problems in the last year. QoL was assessed with the RAND 36-item health survey questionnaire, on five scales: physical functioning, mental health, social functioning, vitality and general health perception. Medication prescribed for 1 to 6 months before the QoL assessment was classified as either evidence-based treatment or under-treatment, according to the 2001 European guidelines on optimal HF treatment. The study had a cross-sectional design. QoL did not differ significantly between evidence-based and under-treated patients, unadjusted or after adjustment for significant patient imbalances. Conventional step-up medication approach in HF may have a positive impact on survival or morbidity, but it seems not beneficial in relation to QoL. Other interventions should be designed to improve QoL of patients with HF.

Multidetector computed tomography-guided treatment strategy in patients with non-ST elevation acute coronary syndromes: a pilot study: Dorgelo J, Willems TP, Geluk CA, van Ooijen PMA, Zijlstra F, Oudkerk M (Department of Radiology, University Hospital Groningen, Groningen, The Netherlands). Eur Radiol 2005;15:708–713

Multidetector computed tomography-guided treatment strategy in patients with non-ST elevation acute coronary syndromes: a pilot study: Dorgelo J, Willems TP, Geluk CA, van Ooijen PMA, Zijlstra F, Oudkerk M (Department of Radiology, University Hospital Groningen, Groningen, The Netherlands). Eur Radiol 2005;15:708–713

Morbidity of Chin Bone Transplants Used for Reconstructing Alveolar Defects in Cleft Patients

The aim of this study was to evaluate the objective and subjective morbidity of symphyseal chin bone harvesting used for reconstruction of alveolar defects in young cleft patients. All patients who had undergone chin bone harvesting for alveolar cleft reconstruction in the period from 1992 through 2000 at the Department of Oral and Maxillofacial Surgery of the University Hospital Groningen, Groningen, The Netherlands, were invited to participate in this retrospective study.Patients' acceptance, perioperative and postoperative morbidity were evaluated. A survey of the medical records was performed. In addition, the patients completed a questionnaire for their appreciation of the procedure. They were also subjected to a clinical and radiographic examination. Thirty patients (21 males and 9 females; mean age 11.8 +/- 3.6 years) participated in this study. Neither the medical records nor the experiences of the patients showed significant morbidity. The procedure was appreciated with 6.8 +/- 3.5 (scale 0 to 10). Postoperative pain was scored as 1.2 +/- 2.5 (scale 0 to 10). Three patients reported transient sensory disturbances at the donor site. Two patients showed a slight sensibility disorder in the symphyseal region. In three patients, an endodontic problem had developed in a lower incisor. This study showed that chin bone harvesting for reconstructing alveolar cleft in young patients is a well-accepted procedure with low objective and subjective morbidity. Notwithstanding this low morbidity, the patients (and their parents) have to be informed about the risk of objective and subjective disturbances of the sensibility in the donor region and the risk of dental pulp necrosis.

Good clinical practice: a plea for nuclear medicine

aDivision of Nuclear Medicine, Ghent University Hospital, Belgium bDepartment of Nuclear Medicine and Molecular Imaging, Groningen University Hospital, The Netherlands Correspondence to Prof. Dr. Andreas Otte, Institute of Nuclear Medicine, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium Tel: +32 9 240 3028; fax: +32 9 240 3807; e-mail: [email protected]

Functional outcome 5 years after non-operative treatment of type A spinal fractures

This study was conducted to study the functional outcome after non-operative treatment of type A thoracolumbar spinal fractures without neurological deficit. Functional outcome was determined following the International Classification of Functioning, Disability and Health, measuring restrictions in body function and structure, restrictions in activities, and restrictions in participation/quality of life. All patients were treated non-operatively for a type A thoracolumbar (Th11-L4) spinal fracture at the University Hospital Groningen, The Netherlands. Thirty-three of the eighty-one selected patients agreed to participate in the study (response-rate 41%). Respondents were older than non-respondents (mean 50.5 years vs. 39.2 years), but did not differ from each other concerning injury-related variables. Patients with a neurological deficit were excluded. Treatment consisted either of mobilisation without brace, or of bedrest followed by wearing a brace. Restrictions in body function and structure were measured by physical tests (dynamic lifting test and bicycle ergometry test); restrictions in activities were measured by means of questionnaires, the Roland Morris Disability Questionnaire (RMDQ) and Visual Analogue Scale Spine Score (VAS). Restrictions in participation/quality of life were assessed with the Short Form 36 (SF-36) and by means of return to work status. Thirty-seven per cent of the patients were not able to perform the dynamic lifting test within normal range. In the ergometry test, 40.9% of the patients performed below the lowest normal value, 36.4% of the patients achieved a high VO(2)-max. Mean RMDQ-score was 5.2, the mean VAS-score was 79. No significant differences between patients and healthy subjects were found in SF-36 scores, neither were differences found between braced and unbraced patients in any of the outcome measures. Concerning the return to work status, 10% of the subjects had stopped working and received social security benefits, 24% had arranged changes in their work and 14% had changed their job. We conclude that patients do reasonably well 5 years after non-operative treatment of a thoracolumbar fracture, although outcome is diverse in the different categories and physical functioning seems restricted in a considerable number of patients.

Long-Term Outcomes After Preeclampsia

University Hospital Groningen, Groningen, The Netherlands Correspondence: Mariëlle G. van Pampus, MD, PhD, Department of Gynaecology and Obstetrics, University Hospital Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. E-mail: [email protected]

Genetic variation in the bleomycin hydrolase gene and bleomycin-induced pulmonary toxicity in germ cell cancer patients

Use of bleomycin as a cytotoxic agent is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BMH). An 1450A>G polymorphic site in the BMH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain, including the polymorphic site, reduces enzymatic activity. We investigated the relation between the BMH genotype and the risk of bleomycin-induced pneumonitis (BIP). From male germ cell cancer patients, treated with bleomycin-containing chemotherapy at the University Hospital Groningen, The Netherlands, between 1977 and 2003, data were collected on age, cumulative bleomycin dose, pretreatment creatinine clearance, pulmonary metastases, lung function parameters, and occurrence of BIP. BIP was defined as: death due to BIP, or presence of clinical and/or radiographic signs of BIP during or following treatment. Polymerase chain reaction and restriction fragment length polymorphism were used to determine the BMH genotype. BIP developed in 38 (11%) of 340 patients; four of these cases were fatal. BMH genotype distribution did not differ between patients with and those without BIP. Patients with BIP were older and had a lower pretreatment creatinine clearance. Changes in pulmonary function tests were similar in patients with different genotypes. The BMH genotype was not associated with the development of BIP nor with changes in pulmonary function tests. Since renal function is important for bleomycin pharmacokinetics, variations in renal clearance may have obscured significant effects of the BMH genotype.

PACS storage requirements—influence of changes in imaging modalities

In current radiology departments, imaging modalities are changing rapidly. One reason for these changes is the continuous technical development providing new imaging modalities with higher spatial and temporal resolution and increased capabilities. Another important reason for change is the replacement of non-digital modalities by digital DICOM modalities to ensure easy storage into the Picture Archiving and Communication System (PACS). Besides the impact on working procedures for both radiologists and technologists, these changes in imaging modalities also influence the storage requirements of the PACS. In the University Hospital Groningen, digital archiving of imaging data started late 1999. From this time on, monthly production figures were collected from different modality types and the dates of changes in imaging modalities were recorded. Our results show that increase in data production is not limited to the recent advancement of multi-detector computed tomography (MDCT), but also new ultrasound (US) devices, magnetic resonance imaging (MRI), and X-ray angiography (XA) could have major impact on the storage capacity requirements. Our measurements show that PACS storage capacity planning should take into account a large margin for growth because of image modality replacement.

Improving compliance with hospital antibiotic guidelines: a time-series intervention analysis

This study investigated the impact of a combined intervention strategy to improve antimicrobial prescribing at University Hospital Groningen. For the intervention, the antimicrobial treatment guidelines were updated and disseminated in paperback and electronic format. The credibility of the guidelines was improved by consultation with users. In a second phase, academic detailing (AD) was used to improve specific areas of low compliance with the guidelines. Prescribing data were prospectively collected for 2869 patients receiving 7471 prescriptions for an antimicrobial for an infection covered by the guidelines between July 2001 and September 2003. After collection of baseline data, the guidelines were actively disseminated in February 2002. Next, after a 5 month interval, a second intervention, i.e. an AD approach, addressed suboptimal prescribing of ciprofloxacin and co-amoxiclav. Segmented regression analysis was used to analyse the interrupted time-series data. At baseline, compliance with the drug choice guidelines was 67%. The first intervention showed a significant change in the level of compliance of +15.5% (95% CI: 8%; 23%). AD did not lead to statistically significant additional changes in already high levels +12.5% (95% CI:-3%; 28%) of compliance. Post-intervention compliance was stable at 86%. Updating the guidelines in close collaboration with the specialists involved followed by active dissemination proved to be an efficient way to improve compliance with guideline recommendations. An 86% compliance level was achieved in this study without compulsory measures. A ceiling effect may have limited the added value of AD.

TOLTERODINE TREATMENT FOR CHILDREN WITH SYMPTOMS OF URINARY URGE INCONTINENCE SUGGESTIVE OF DETRUSOR OVERACTIVITY: RESULTS FROM 2 RANDOMIZED, PLACEBO CONTROLLED TRIALS

We report the results of the first 2 large randomized controlled trials designed to evaluate the efficacy and safety of tolterodine extended release in children 5 to 10 years old with symptoms of urinary urge incontinence suggestive of detrusor overactivity. Two double-blind, placebo controlled trials were conducted sequentially. Children 5 to 10 years old with incontinence suggestive of detrusor overactivity (1 or more diurnal incontinence episodes per 24 hours) were randomized to tolterodine (2 mg daily) or placebo for 12 weeks. The primary end point was the change from baseline to week 12 in the number of incontinence episodes per week. Changes from baseline in the number of voids per 24 hours and volume of urine per void were also evaluated. Exploratory analyses were conducted to determine whether particular subsets of patients showed differential responses to treatment. A total of 224 and 487 children (mean age 8 years) were randomized to placebo and tolterodine, respectively. Differences in the number of incontinence episodes per week, voids per 24 hours, and volume of urine per void between tolterodine and placebo did not reach statistical significance. This finding may be explained by a high placebo response and under dosage of tolterodine among children with greater body weight. Tolterodine was well tolerated. Analysis of the primary efficacy outcome did not reveal a statistically significant effect of treatment. However, secondary analyses demonstrated that tolterodine was well tolerated among 5 to 10-year-old children with diurnal incontinence. Exploratory analyses also showed that children weighing 35 kg or less with detrusor overactivity characterized by incontinence and/or frequent voiding benefited most from tolterodine treatment, suggesting that a weight adjusted dosing regimen may be required for optimal response among older and heavier children.