Publications by authors named "Audrey A A Fiddelers"

23 Publications

  • Page 1 of 1

The impact of prehospital time intervals on mortality in moderately and severely injured patients.

J Trauma Acute Care Surg 2021 Aug 16. Epub 2021 Aug 16.

Department of Surgery University Medical Center Utrecht, Utrecht, The Netherlands Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands Network of Acute Care Limburg, Maastricht University Medical Center, Maastricht, The Netherlands Center for Artificial Intelligence in Medicine & Imaging, Stanford, US Department of Surgery, Diakonessenhuis Utrecht/Zeist/Doorn, Utrecht, The Netherlands.

Background: Modern trauma systems and Emergency Medical Services aim to reduce prehospital time intervals to achieve optimal outcomes. However, current literature remains inconclusive on the relationship between time to definitive treatment and mortality. The aim was to investigate the association between prehospital time and mortality.

Methods: All moderately and severely injured trauma patients (i.e., patients with an Injury Severity Score of 9 or greater) that were transported from the scene of injury to a trauma center by ground ambulances of the participating Emergency Medical Services between 2015 and 2017 were included. Exposures of interest were total prehospital time, on-scene time, and transport time. Outcomes were 24 h and 30-day mortality. Generalized linear models including inverse probability weights for several potential confounders were constructed. A generalized additive model was constructed to enable visual inspection of the association.

Results: We included 22,525 moderately and severely injured patients. 24 h and 30-day mortality were 1.3% and 7.3%, respectively. On-scene time per minute was significantly associated with 24 h (relative risk [RR] 1.029; 95% CI, 1.018-1.040) and 30-day mortality (RR 1.013; 1.008-1.017). We found that this association was also present in patients with severe injuries, traumatic brain injury, severe abdominal injury, and stab or gunshot wound. An on-scene time of 20 minutes or longer demonstrated a strong association with 24 h (RR 1.797; 1.406-2.296) and 30-day mortality (RR 1.298; 1.180-1.428). Total prehospital (24 h: RR 0.998; 0.990-1.007; 30-day: RR 1.000, 0.997-1.004) and transport (24 h: RR 0.996; 0.982-1.010; 30-day: RR 0.995; 0.989-1.001) time were not associated with mortality.

Conclusions: A prolonged on-scene time is associated with mortality in moderately and severely injured patients, which suggests that a reduced on-scene time may be favorable for these patients. Additionally, transport time was found not to be associated with mortality.

Level Of Evidence: Prognostic study, level III.
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http://dx.doi.org/10.1097/TA.0000000000003380DOI Listing
August 2021

Priority accuracy by dispatch centers and Emergency Medical Services professionals in trauma patients: a cohort study.

Eur J Trauma Emerg Surg 2021 May 21. Epub 2021 May 21.

Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.

Purpose: Priority-setting by dispatch centers and Emergency Medical Services professionals has a major impact on pre-hospital triage and times of trauma patients. Patients requiring specialized care benefit from expedited transport to higher-level trauma centers, while transportation of these patients to lower-level trauma centers is associated with higher mortality rates. This study aims to evaluate the accuracy of priority-setting by dispatch centers and Emergency Medical Services professionals.

Methods: This observational study included trauma patients transported from the scene of injury to a trauma center. Priority-setting was evaluated in terms of the proportion of patients requiring specialized trauma care assigned with the highest priority (i.e., sensitivity), undertriage, and overtriage. Patients in need of specialized care were defined by a composite resource-based endpoint. An Injury Severity Score ≥ 16 served as a secondary reference standard.

Results: Between January 2015 and December 2017, records of 114,459 trauma patients were collected, of which 3327 (2.9%) patients were in need of specialized care according to the primary reference standard. Dispatch centers and Emergency Medical Services professionals assigned 83.8% and 74.5% of these patients with the highest priority, respectively. Undertriage rates ranged between 22.7 and 65.5% in the different prioritization subgroups. There were differences between dispatch and transport priorities in 17.7% of the patients.

Conclusion: The majority of patients that required specialized care were assigned with the highest priority by the dispatch centers and Emergency Medical Services professionals. Highly accurate priority criteria could improve the quality of pre-hospital triage.
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http://dx.doi.org/10.1007/s00068-021-01685-1DOI Listing
May 2021

The impact of the Trauma Triage App on pre-hospital trauma triage: design and protocol of the stepped-wedge, cluster-randomized TESLA trial.

Diagn Progn Res 2020 18;4:10. Epub 2020 Jun 18.

Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Field triage of trauma patients is crucial to get the right patient to the right hospital within a particular time frame. Minimization of undertriage, overtriage, and interhospital transfer rates could substantially reduce mortality rates, life-long disabilities, and costs. Identification of patients in need of specialized trauma care is predominantly based on the judgment of Emergency Medical Services professionals and a pre-hospital triage protocol. The Trauma Triage App is a smartphone application that includes a prediction model to aid Emergency Medical Services professionals in the identification of patients in need of specialized trauma care. The aim of this trial is to assess the impact of this new digital approach to field triage on the primary endpoint undertriage.

Methods: The Trauma triage using Supervised Learning Algorithms (TESLA) trial is a stepped-wedge cluster-randomized controlled trial with eight clusters defined as Emergency Medical Services regions. These clusters are an integral part of five inclusive trauma regions. Injured patients, evaluated on-scene by an Emergency Medical Services professional, suspected of moderate to severe injuries, will be assessed for eligibility. This unidirectional crossover trial will start with a baseline period in which the default pre-hospital triage protocol is used, after which all clusters gradually implement the Trauma Triage App as an add-on to the existing triage protocol. The primary endpoint is undertriage on patient and cluster level and is defined as the transportation of a severely injured patient (Injury Severity Score ≥ 16) to a lower-level trauma center. Secondary endpoints include overtriage, hospital resource use, and a cost-utility analysis.

Discussion: The TESLA trial will assess the impact of the Trauma Triage App in clinical practice. This novel approach to field triage will give new and previously undiscovered insights into several isolated components of the diagnostic strategy to get the right trauma patient to the right hospital. The stepped-wedge design allows for within and between cluster comparisons.

Trial Registration: Netherlands Trial Register, NTR7243. Registered 30 May 2018, https://www.trialregister.nl/trial/7038.
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http://dx.doi.org/10.1186/s41512-020-00076-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302135PMC
June 2020

Long-term Patient-reported Quality of Life and Pain After a Multidisciplinary Clinical Pathway for Elderly Patients With Hip Fracture: A Retrospective Comparative Cohort Study.

Geriatr Orthop Surg Rehabil 2019 6;10:2151459319841743. Epub 2019 Jun 6.

Department of Trauma Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.

Introduction: There is an increase in incidence of hip fractures in the ageing population. The implementation of multidisciplinary clinical pathways (MCP) has proven to be effective in improving the care for these frail patients, and MCP tends to be more effective than usual care (UC). The aim of this study was to analyze potential differences in patient-reported outcome among elderly patients with hip fractures who followed MCP versus those who followed UC.

Materials And Methods: This retrospective cohort study included patients aged 65 years or older with a low-energy hip fracture, who underwent surgery in the Maastricht University Medical Center, Maastricht, the Netherlands. Two cohorts were analyzed; the first one had patients who underwent UC in 2012 and the second one contained patients who followed MCP in 2015. Collected data regarded demographics, patient-reported outcomes (Short Form 12 [SF-12] and the Numeric Rating Scale [NRS] to measure pain), and patient outcome.

Results: This cohort study included 398 patients, 182 of them were included in the MCP group and 216 were in the UC group. No differences in gender, age, or American Society of Anesthesiologists classification were found between the groups. No significant differences were found in SF-12 and the NRS data between the MCP group and UC group. In the MCP group, significantly lower rates of postoperative complications were found than in the UC group, but mortality within 30 days and one year after the hip fracture was similar in both groups.

Discussion: Although the effects of hip fractures in the elderly on patient-reported outcome, pain and quality of life have been addressed in several recent studies, the effects of MCP on long-term outcome was unclear.

Conclusion: A multidisciplinary clinical pathway approach for elderly patients with a hip fracture is associated with a reduced time to surgery and reduced postoperative complications, while no differences were found in quality of life, pain, or mortality.
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http://dx.doi.org/10.1177/2151459319841743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557012PMC
June 2019

Long-term functional outcome after a low-energy hip fracture in elderly patients.

J Orthop Traumatol 2019 04 11;20(1):20. Epub 2019 Apr 11.

Department of Trauma Surgery, Maastricht University Medical Center+, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands.

Background: The incidence of hip fractures is increasing. Elderly patients with a hip fracture frequently present with comorbidities, which are associated with higher mortality rates. Clinical studies regarding long-term functional outcome and mortality in hip fractures are rare. The aim of this study was to analyse the functional outcome and the mortality rate after a follow-up of 5 years in elderly patients with a hip fracture.

Materials And Methods: This combined retrospective and cross-sectional study included patients aged 65 years or older with a low energy hip fracture who underwent surgery in the Maastricht University Medical Center+, the Netherlands. Data such as demographics and mortality rates were retrospectively collected and functional outcome (i.e. mobility, pain, housing conditions and quality of life) was assessed by a questionnaire.

Results: Two hundred and sixteen patients were included in this study (mean age 82.2, SD ± 7.5). No significant differences were found in pain before hip fracture and after 1-year and 5-year follow-ups. Long-term functional outcome deteriorated after a hip fracture, with a significant increase in the use of walking aids (p < 0.001), a significant decrease of patients living in a private home (p < 0.001), and a low physical quality of life (SF-12 PCS = 27.1). The mortality incidences after 30-day, 1-year and 5-year follow-ups were 7.9%, 37.0% and 69.4%, respectively.

Conclusion: Long-term functional outcome in elderly patients with hip fractures significantly deteriorated, with an increased dependency for mobility and housing conditions and a decreased physical quality of life. In addition, hip fractures are associated with high mortality rates at the 5-year follow-up.

Level Of Evidence: Level III, a retrospective cohort study.
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http://dx.doi.org/10.1186/s10195-019-0529-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459450PMC
April 2019

Procedure-Specific Pain Intensity Four Days After Day Surgery and the Relationship with Preoperative Pain: A Prospective Cohort Study.

Anesth Pain Med 2018 Dec 17;8(6):e81366. Epub 2018 Nov 17.

Department of Anesthesiology and Pain Medicine, Jessa Hospital, Hasselt, Belgium.

Background: Identification of painful procedures is essential for the development of procedure-specific pain-treatment schedules. The aim of this study was firstly, to analyze the prevalence of acute postsurgical pain (APSP) after various types of day surgery on the fourth postoperative day, and secondly, to assess the predictive value of preoperative pain for the development of APSP after different types of surgical procedures.

Methods: From November 2008 to April 2010, patients scheduled for elective day surgery were enrolled in this prospective cohort study. Data were collected one week preoperatively and four days postoperatively. The 11-point Numeric Rating Scale (NRS) was used for pain measurement. Moderate pain was defined as an NRS 4 to 5, and severe pain as an NRS > 5. The predictive value of preoperative pain for development of APSP was analyzed using a univariate logistic regression, stratified for the surgical procedure.

Results: From a total of 1123 included patients, 182 patients experienced moderate pain (16.3%) and 136 patients experienced severe pain (12.1%) on the fourth postoperative day. A large procedure-specific variability in APSP was observed, with shoulder, anal and dental surgery associated with the highest pain levels. Overall, preoperative pain significantly predicted postoperative pain on the fourth day (OR 4.45). This predictive value showed a procedure-specific variation and was not noted after various well-defined procedures.

Conclusions: The prevalence of moderate to severe APSP was high four days after day surgery and showed a significant procedure-specific variation. Furthermore, there was a strong relationship between preoperative and postoperative pain, likewise characterized by a significant procedure-specific variation.
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http://dx.doi.org/10.5812/aapm.81366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347732PMC
December 2018

Beware of the force of the horse: mechanisms and severity of equestrian-related injuries.

Eur J Emerg Med 2019 Apr;26(2):133-138

Surgery, VieCuri Medical Centre, Venlo.

Background: Equestrian-related injuries (ERIs) are relatively severe compared with injuries in other popular sports. Previous studies on epidemiology of ERIs vary widely and mainly focus on incidence instead of severity of the injury.

Purpose: The aim of this study was to determine incidence, mechanisms and severity of ERIs in two Dutch hospitals (level 1 and level 2 trauma centers) over a 5-year period.

Patients And Methods: All patients with ERIs who visited the emergency departments of VieCuri Medical Centre in Venlo and Maastricht University Medical Centre+ in Maastricht, The Netherlands, between July 2010 and June 2015 were retrospectively included. Clinical data were extracted from medical records.

Results: Most ERIs occurred in mounted riders (646 events; 68%); 94.9% of which involved a fall. Being kicked (42.5%) or trapped (30.1%) was the most common cause of injury in unmounted riders. Most frequently injured body parts were the upper extremities (43.8%) in mounted riders and lower extremities (40.5%) in the unmounted group. A relatively high percentage of facial injuries (9.7%) were found in the unmounted group. Seventeen per cent of all ERIs required admission. The median Injury Severity Score was 5 in the admitted population and 1 in the total population.

Conclusion: Horseback riding is a risky activity. Prior studies particularly studied admitted patients in level 1 trauma centers outside of Europe and demonstrated a high risk of significant injury. However, our study demonstrates that these studies in selected groups might have overestimated the severity of ERIs in the general population.
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http://dx.doi.org/10.1097/MEJ.0000000000000511DOI Listing
April 2019

Prevalence and Predictors of Patient Nonadherence to Pharmacological Acute Pain Therapy at Home After Day Surgery: A Prospective Cohort Study.

Pain Pract 2018 02 16;18(2):194-204. Epub 2017 Jun 16.

Department of Anesthesiology and Pain Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Good adherence to prescribed analgesics can be crucial to suppress or even prevent acute postoperative pain after day surgery. The aim of this study was to analyze prevalence and predictors of analgesic nonadherence after day surgery.

Methods: Elective patients scheduled for day surgery were prospectively enrolled from November 2008 to April 2010. Outcome parameters were measured by using questionnaire packages at 2 time points: 1 week preoperatively and 4 days postoperatively. The primary outcome parameter was analgesic nonadherence. Adherence was defined according to the patient's response to the questionnaire item "analgesia use as prescribed": full adherence, "yes"; partial adherence, "yes, sometimes"; nonadherence, "no." Bivariate and multivariate logistic regression analyses were performed to identify predictors of analgesic nonadherence.

Results: A total of 1,248 patients were included. The prevalence rates of analgesic nonadherence and partial adherence were 21.6% and 20.0%, respectively, in the total study population but dropped to 9.4% and 19.8%, respectively, in patients with moderate to severe pain. Low postoperative pain intensity and short duration of surgery were the most important predictors of analgesic nonadherence. The most important preoperative predictors for analgesic nonadherence were low preoperative pain intensity, low preoperative expectations of pain, and low fear of short-term effects of surgery.

Conclusion: Analgesic nonadherence and partial adherence are common after day surgery but decrease as average pain intensity increases. Patients at risk for analgesic nonadherence can be identified during the preoperative period based on preoperative pain intensity, preoperative expectations of pain, and fear of surgery.
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http://dx.doi.org/10.1111/papr.12589DOI Listing
February 2018

External Validation and Modification of a Predictive Model for Acute Postsurgical Pain at Home After Day Surgery.

Clin J Pain 2017 05;33(5):405-413

*Department of Anesthesiology and Pain Medicine, Jessa Hospital, Hasselt, Belgium Departments of †Anesthesiology and Pain Medicine ∥Clinical Epidemiology and Medical Technology Assessment ¶Clinical Psychological Science, Maastricht University Medical Center+ ‡Network Acute Care Limburg, Maastricht, The Netherlands §Department of Anesthesia/ICU, Pain & Palliative Care, Hamad Medical Corporation, Doha, Qatar.

Objectives: In 2009, Gramke and colleagues have described predictive factors to preoperatively detect those at risk for moderate to severe acute postsurgical pain (APSP) after day surgery. The aim of the present study is to externally validate this initial model and to improve and internally validate a modified version of this model.

Materials And Methods: Elective patients scheduled for day surgery were prospectively enrolled from November 2008 to April 2010. Model discrimination was quantified using the area under the receiver operating characteristic curve (AUC). Model calibration was assessed by visual inspection of the calibration plot. Subsequently, we modified (different assignment of type of surgery, different cutoff for moderate to severe APSP, continuous of dichotomized variables and testing of additional variables) and internally validated this model by standard bootstrapping techniques.

Results: A total of 1118 patients were included. The AUC for the original model was 0.81 in the derivation data set and 0.72 in our validation data set. The model showed poorly calibrated risk predictions. The AUC of the modified model was 0.82 (optimism-corrected AUC=0.78). This modified model showed good calibration.

Conclusions: The original prediction model of Gramke and colleagues performed insufficiently on our cohort of outpatients with respect to discrimination and calibration. Internal validation of a modified model shows promising results. In this model, preoperative pain, patient derived expected pain, and different types of surgery are the strongest predictors of moderate to severe APSP after day surgery.
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http://dx.doi.org/10.1097/AJP.0000000000000413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638419PMC
May 2017

Prevalence and Predictive Factors of Chronic Postsurgical Pain and Global Surgical Recovery 1 Year After Outpatient Knee Arthroscopy: A Prospective Cohort Study.

Medicine (Baltimore) 2015 Nov;94(45):e2017

From the Department of Anesthesiology and Pain Treatment (DMNH, AAAF, EAJ, H-FG, MAEM, WFFAB); Department of Orthopedic Surgery, Maastricht University Medical Center+, Maastricht, The Netherlands (PJE); and Department of Anesthesiology, ICU and Perioperative Medicine, Hamad Medical Corporation, Qatar (MAEM).

Outpatient knee arthroscopy is one of the most commonly performed surgical procedures. Previous research has demonstrated that chronic postsurgical pain (CPSP) after outpatient surgery is prevalent. Our objective was to determine the prevalence and predictive factors of CPSP and Global Surgical Recovery (GSR) 1 year after knee arthroscopy.A prospective longitudinal cohort study was performed. Patients were included during an 18-month period. Data were collected by using 3 questionnaires: at 1 week preoperatively, 4 days postoperatively, and 1 year postoperatively. A value of >3 on an 11-point numeric rating scale (NRS) was defined as moderate to severe pain. A score of ≤80% on the Global Surgical Recovery Index was defined as poor GSR. Stepwise logistic regression analysis was performed to determine which variables were predictors for CPSP and poor GSR.The prevalence of moderate to severe preoperative pain in patients undergoing knee arthroscopy (n = 104) was 71.2%, of acute postsurgical pain 37.5%, and of CPSP 32.7%. Risk factors for CPSP were the presence of preoperative pain and preoperative analgesic use, with odds ratios of 6.31 (1.25-31.74) and 4.36 (1.58-12.07), respectively. The prevalence of poor GSR 1 year after outpatient knee arthrosocpy was 50.0%. Poor GSR 4 days after the surgery was a risk factor with an odds ratio of 8.38 (0.92-76.58) and quality of life 4 days after surgery was a protective factor with and odds ratio of 0.10 (0.02-0.64).Both CPSP and poor GSR are common 1 year after knee arthroscopy. Patients at risk for CPSP can be identified during the preoperative phase. Prediction of poor GSR 1 year after surgery is mainly related to early postoperative recovery.
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http://dx.doi.org/10.1097/MD.0000000000002017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912294PMC
November 2015

Prevalence and Predictive Factors of Chronic Postsurgical Pain and Poor Global Recovery 1 Year After Outpatient Surgery.

Clin J Pain 2015 Dec;31(12):1017-25

Departments of *Anesthesiology and Pain Treatment §Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center+(a.k.a. MUMC+) †Department of Clinical Psychological Science, Maastricht University, Maastricht, The Netherlands ‡Department of Anaesthesiology, Jessa Hospital, Hasselt, Belgium ∥Department of Anesthesiology, ICU and Perioperative Medicine, Hamad Medical Corporation, Doha, Qatar.

Objectives: To prospectively describe the prevalence and predictive factors of chronic postsurgical pain (CPSP) and poor global recovery in a large outpatient population at a university hospital, 1 year after outpatient surgery.

Materials And Methods: A prospective longitudinal cohort study was performed. During 18 months, patients presenting for preoperative assessment were invited to participate. Outcome parameters were measured by using questionnaires at 3 timepoints: 1 week preoperatively, 4 days postoperatively, and 1 year postoperatively. A value of >3 on an 11-point numeric rating scale was considered to indicate moderate to severe pain. A score of ≤80% on the Global Surgical Recovery Index was defined as poor global recovery.

Results: A total of 908 patients were included. The prevalence of moderate to severe preoperative pain was 37.7%, acute postsurgical pain 26.7%, and CPSP 15.3%. Risk factors for the development of CPSP were surgical specialty, preoperative pain, preoperative analgesic use, acute postoperative pain, surgical fear, lack of optimism, and poor preoperative quality of life. The prevalence of poor global recovery was 22.3%. Risk factors for poor global recovery were recurrent surgery because of the same pathology, preoperative pain, preoperative analgesic use, surgical fear, lack of optimism, poor preoperative and acute postoperative quality of life, and follow-up surgery during the first postoperative year.

Discussion: Moderate to severe CPSP after outpatient surgery is common, and should not be underestimated. Patients at risk for developing CPSP can be identified during the preoperative phase.
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http://dx.doi.org/10.1097/AJP.0000000000000207DOI Listing
December 2015

Validation of the surgical fear questionnaire in adult patients waiting for elective surgery.

PLoS One 2014 24;9(6):e100225. Epub 2014 Jun 24.

Department of Anesthesiology and Pain Management, Maastricht University Medical Center+, Maastricht, the Netherlands; Department of Anesthesia/ICU, Pain and Palliative Care, Hamad Medical Corporation, Doha, Qatar.

Objectives: Because existing instruments for assessing surgical fear seem either too general or too limited, the Surgical Fear Questionnaire (SFQ) was developed. The aim of this study is to assess the validity and reliability of the SFQ.

Methods: Based on existing literature and expert consultation the ten-item SFQ was composed. Data on the SFQ were obtained from 5 prospective studies (N = 3233) in inpatient or day surgery patients. These data were used for exploratory factor analysis (EFA), confirmatory factor analysis (CFA), reliability analysis and validity analysis.

Results: EFA in Study 1 and 2 revealed a two-factor structure with one factor associated with fear of the short-term consequences of surgery (SFQ-s, item 1-4) and the other factor with fear of the long-term consequences of surgery (SFQ-l, item 5-10). However, in both studies two items of the SFQ-l had low factor loadings. Therefore in Study 3 and 4 the 2-factor structure was tested and confirmed by CFA in an eight-item version of the SFQ. Across all studies significant correlations of the SFQ with pain catastrophizing, state anxiety, and preoperative pain intensity indicated good convergent validity. Internal consistency (Cronbach's alpha) was between 0.765-0.920 (SFQ-total), 0.766-0.877 (SFQ-s), and 0.628-0.899 (SFQ-l). The SFQ proved to be sensitive to detect differences based on age, sex, education level, employment status and preoperative pain intensity.

Discussion: The SFQ is a valid and reliable eight-item index of surgical fear consisting of two subscales: fear of the short-term consequences of surgery and fear of the long-term consequences.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100225PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069058PMC
March 2015

Pharmacokinetics and tolerability of nasal versus intravenous midazolam in healthy Dutch volunteers: a single-dose, randomized-sequence, open-label, 2-period crossover pilot study.

Clin Ther 2011 Dec 10;33(12):2022-8. Epub 2011 Nov 10.

Department of Clinical Pharmacology & Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Background: Intranasal (IN) midazolam is a potential alternative to rectal diazepam for the acute treatment of epileptic seizures.

Objective: The purpose of this pilot study was to investigate the pharmacokinetics and tolerability of IN midazolam (50 mg/mL) compared with intravenous (IV) midazolam (2.5 mg) in healthy adult volunteers.

Methods: In this single-dose, randomized-sequence, open-label, 2-period crossover pilot study subjects were randomly assigned to receive IN or IV midazolam, with a washout period of at least 5 days between treatments. The 50-mg/mL IN midazolam formulation consisted of 5 mg midazolam base per 0.1 mL (1 spray) and was administered once in 1 nostril. The IV midazolam solution (2.5 mg) was infused over 10 seconds. Blood samples were taken before and at regular intervals up to 240 minutes after dosing. Pharmacokinetic data (ie, C(max), T(max), t(½), and AUC) were analyzed using a 2-compartment model.

Results: Of 9 volunteers screened and enrolled, 7 completed the study (mean age 34.1 [9.0] years; mean weight, 68.6 [10.4] kg, range 53-89 kg; 6 men, 3 women; all white). The mean C(max) of 78 (40) ng/mL was reached 44 minutes after IN administration, whereas the mean C(max) was 51 (5) ng/mL after IV administration. The mean estimated C(t=5 min) was 31.4 (28.1) ng/mL after IN administration. The elimination t(½) was 1.9 (0.41) hours for IN midazolam and 2.3 (0.19) hours for IV midazolam. The bioavailability of IN midazolam was 82%. There were few adverse events, with a local burning feeling in the nose being the most reported event (6 of 7 subjects).

Conclusions: In this select group of healthy volunteers, concentrations of midazolam >30 ng/mL were reached within 5 minutes of IN administration at a dose of 5 mg/0.1 mL. A burning feeling in the nostril was the main adverse effect. Additional research is needed to evaluate the safety profile, convenience, satisfaction, and efficacy of nasal midazolam in the treatment of adults with seizures. This trial is registered at www.isrctn.org, No. ISRCTN79059168.
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http://dx.doi.org/10.1016/j.clinthera.2011.10.012DOI Listing
December 2011

During IVF treatment patient preference shifts from singletons towards twins but only a few patients show an actual reversal of preference.

Hum Reprod 2011 Aug 5;26(8):2092-100. Epub 2011 May 5.

Department of Clinical Epidemiology and Medical Technology Assessment, Research Institute Grow and Development, and Care and Public Health Research Institute, PO Box 5800, 6202 AZ Maastricht, The Netherlands.

Background: Knowledge of patients' preferences for elective single embryo transfer (eSET) or double embryo transfer (DET) and for singletons or twins is of great importance in counselling for embryo transfer (ET) strategies. In this study, the stability of IVF patients' preferences over time for either a healthy single child or healthy twins was measured and we investigated which factors could explain preference shifts.

Methods: Infertile women (n = 177) who participated in an RCT comparing one cycle eSET with one cycle DET were included. A satisfaction questionnaire was developed to measure patient preferences and attitudes at two moments in time, i.e. at 2 weeks before ET and at 2 weeks following ET, after the results of the pregnancy test. Regression analysis examined the effect of several variables on preference shifts.

Results: Before ET, most patients expressed a preference for a singleton, whereas most patients were indifferent 2 weeks after ET, resulting in an overall preference shift towards twins (P = 0.002; n = 145). Overall, 62% of patients showed a preference shift. Preference shifts were explained by patients' global satisfaction of the information given by the fertility clinic staff received by the fertility clinic staff, and an interaction between the occurrence of pregnancy and transfer policy (eSET or DET).

Conclusions: In general, patients' preferences for a singleton or twins are not stable during IVF treatment. Possible explanations of a shift in preference are that pregnant patients attuned their preferences to what they expect their pregnancy to result in, whereas non-pregnant patients shifted towards a preference for twins in order to be able to fulfil their ultimate child wish.
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http://dx.doi.org/10.1093/humrep/der127DOI Listing
August 2011

Pharmacokinetics, analgesic effect, and tolerability of a single preprocedural dose of intranasal fentanyl in patients undergoing drain removal after breast reduction or augmentation surgery: A prospective, randomized, double-blind, placebo-controlled study.

Clin Ther 2010 Jul;32(7):1427-36

Department of Clinical Pharmacology and Toxicology, Maastricht University Medical Centre, the Netherlands.

Background: Although acetaminophen is used to reduce pain after breast reduction or augmentation surgery, pain during the removal of the surgical drains is typically not specifically treated. Intranasally administered fentanyl may be suitable for pain control during removal of drains. The reported therapeutic window of fentanyl is between 0.2 and 1.2 ng/mL.

Objective: The aim of this study was to evaluate the analgesic effect, tolerability, and pharmacokinetics of a single preprocedural dose of intranasal fentanyl administered before removal of surgical drains in patients who had undergone breast reduction or augmentation surgery.

Methods: This was a randomized, double-blind, prospective study in healthy women (American Society of Anesthesiologists physical status I or II) between the ages of 18 and 65 years who were scheduled to undergo removal of surgical drains 1 to 4 days after breast reduction or augmentation surgery. A single dose of fentanyl nasal spray 0.05 mg/0.1 mL or placebo (preserved normal saline) 0.1 mL was administered 10 minutes before removal of drains. Because drain removal is generally carried out without specific analgesia, no rescue medication was provided. Pain intensity was measured on a visual analog scale (VAS) from 0 = no pain at all to 100 = worst pain possible. Pain intensity was evaluated immediately before administration of study medication (t = 0), at the time of drain removal (t = 10), and at 15, 20, 25, 40, and 70 minutes after administration of study medication. Safety measures included oxygen saturation, respiratory rate, heart rate, and blood pressure. Local and systemic adverse events were elicited by direct questioning throughout the study. Blood samples for pharmacokinetic analysis were collected at baseline and at 5, 10, 15, 30, 60, and 120 minutes after administration of study medication. The population pharmacokinetic parameters of fentanyl were calculated according to a 1-compartment open model with an iterative 2-stage Bayesian fitting procedure.

Results: Thirty-six women were randomized to treatment, and 33 completed the study. Their mean (SD) age was 39.2 (13.0) years, and their mean weight was 68.9 (10.7) kg. Mean VAS scores at baseline were 14.8 (17.8) for the fentanyl group and 6.0 (9.7) for the placebo group (P = NS); at the time of drain removal, the corresponding VAS scores were 31.0 (20.6) and 33.8 (25.7) (P = NS). Analysis of a random-effects model with mean VAS scores as a function of time as the dependent variable indicated a significant difference in mean VAS scores between the fentanyl and placebo groups (P = 0.006). The overall incidence of adverse events was 39.4% (13/33). Among the 17 patients in the fentanyl group, 8 reported > or =1 adverse event; among the 16 patients in the placebo group, 9 reported > or =1 adverse event. A mean estimated C(max) of 0.184 (0.069) ng/mL was reached at 13.76 (3.56) minutes after administration of intranasal fentanyl. The mean measured C(max) was 0.22 (0.088) ng/mL.

Conclusions: In these women who had undergone breast reduction or augmentation surgery, a single preprocedural dose of intranasal fentanyl was significantly more effective than placebo in reducing pain intensity over the hour after removal of surgical drains. However, there was no significant difference in pain intensity between fentanyl at the time of drain removal and placebo. Intranasal fentanyl was generally well tolerated. At the dose used (0.05 mg), plasma fentanyl concentrations were below the reported therapeutic window.
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http://dx.doi.org/10.1016/j.clinthera.2010.07.001DOI Listing
July 2010

Prevalence and predictors of chronic pain after labor and delivery.

Curr Opin Anaesthesiol 2010 Jun;23(3):295-9

Department of Anaesthesiology and Pain Therapy, Maastricht University Medical Center, Maastricht, The Netherlands.

Purpose Of Review: Labor pain is a complex phenomenon with sensory, emotional, and perceptive components and can be regarded as one of the most serious kinds of pain. Different strategies to approach acute labor pain have been developed. Chronic pain after labor and delivery has not been studied so extensively. In this review recent findings about chronic pain after labor and delivery will be discussed.

Recent Findings: Prevalence rates of chronic pain after cesarean section are between 6 and 18% and after vaginal delivery they are between 4 and 10%. Predictors for chronic pain after cesarean section and delivery are previous chronic pain, general anesthesia and higher postdelivery pain. As labor pain is rated as one of the most serious kinds of acute pain one could make a prediction about chronic pain after labor and delivery. We speculate that effective treatment of this pain with epidural analgesia could prevent the development of chronic pain.

Summary: Treatment of acute pain during labor and delivery is necessary to prevent chronic pain. Future studies should focus on the long-term effects of different analgesic regimens on the development of chronic pain after labor and delivery.
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http://dx.doi.org/10.1097/aco.0b013e32833853e8DOI Listing
June 2010

A review of the clinical pharmacokinetics of opioids, benzodiazepines, and antimigraine drugs delivered intranasally.

Clin Ther 2009 Dec;31(12):2954-87

Department of Clinical Pharmacology, Maastricht University Medical Centre, Maastricht, the Netherlands.

Background: Interest in the development of drug-delivery devices that might improve treatment compliance is growing. A dosage formulation that is easy to use, such as intranasal application with transmucosal absorption, may offer advantages compared with other routes of drug delivery. The literature concerning intranasal application is diffuse, with a large number of published studies on this topic. Some cerebroactive pharmaceuticals delivered intranasally might follow the pathway from the nose to the systemic circulation to the brain. To determine the suitability of these drugs for intranasal drug delivery, a systematic review was performed.

Objective: The aim of this review was to compare the pharmacokinetic properties of intranasal, intravenous, and oral formulations in 3 classes of cerebroactive drugs that might be suitable for intranasal delivery-opioids, benzodiazepines, and antimigraine agents.

Methods: A search of MEDLINE, PubMed, Cumulative Index of Nursing and Allied Health Literature, EMBASE, and Cochrane Database of Systematic Reviews (dates: 1964-April 2009) was conducted for pharmacokinetic studies of drugs that might be suitable for intranasal delivery. A comparison of pharmacokinetic data was made between these 3 routes of administration.

Results: A total of 45 studies were included in this review. Most of the opioids formulated as an intranasal spray reached a T(max) within 25 minutes. The bioavailability of intranasal opioids was high; in general, >50% compared with opioids administered intravenously. Intranasal benzodiazepines had an overall T(max) that varied from 10 to 25 minutes, and bioavailability was between 38% and 98%. T(max) for most intranasal antimigraine drugs varied from 25 to 90 minutes. Intranasal bioavailability varied from 5% to 40%.

Conclusions: This review found that intranasal administration of all 3 classes of drugs was suitable for indications of rapid delivery, and that the pharmacokinetic properties differed between the intranasal, oral, and intravenous formulations (intravenous > intranasal > oral).
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http://dx.doi.org/10.1016/j.clinthera.2009.12.015DOI Listing
December 2009

Cost-effectiveness of seven IVF strategies: results of a Markov decision-analytic model.

Hum Reprod 2009 Jul 24;24(7):1648-55. Epub 2009 Mar 24.

Department of Clinical Epidemiology and Medical Technology Assessment, Academic Hospital Maastricht, PO Box 5800, Maastricht 6202 AZ, The Netherlands.

Background: A selective switch to elective single embryo transfer (eSET) in IVF has been suggested to prevent complications of fertility treatment for both mother and infants. We compared seven IVF strategies concerning their cost-effectiveness using a Markov model.

Methods: The model was based on a three IVF-attempts time horizon and a societal perspective using real world strategies and data, comparing seven IVF strategies, concerning costs, live births and incremental cost-effectiveness ratios (ICERs).

Results: In order to increase pregnancy probability, one cycle of eSET + one cycle of standard treatment policy [STP, i.e. eSET in patients <38 years of age with at least one good quality embryo and double embryo transfer (DET) in the remainder of patients] + one cycle of DET have an ICER of 16,593 euro compared with three cycles of eSET. Furthermore, three STP cycles have an ICER of 17,636 euro compared with one cycle of eSET + one cycle of STP + one cycle of DET, and three DET cycles have an ICER of 26,729 euro compared with three cycles STP.

Conclusions: Our study shows that in patients qualifying for IVF treatment, combining several transfer policies was not cost-effective. A choice has to be made between three cycles of eSET, STP or DET. It depends, however, on society's willingness to pay which strategy is to be preferred from a cost-effectiveness point of view.
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http://dx.doi.org/10.1093/humrep/dep041DOI Listing
July 2009

eSET irrespective of the availability of a good-quality embryo in the first cycle only is not effective in reducing overall twin pregnancy rates.

Hum Reprod 2007 Jun 7;22(6):1669-74. Epub 2007 Apr 7.

Research Institute Growth & Development (GROW), Department of Obstetrics and Gynaecology, Academic Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands.

Introduction: In several clinics, elective single-embryo transfer (eSET) is applied in a selected group of patients based on age and the availability of a good-quality embryo. Whether or not eSET can be applied irrespective of the presence of a good-quality embryo in the first cycle, to further reduce the twin pregnancy rate, remains to be elucidated.

Methods: In patients <38 years two transfer strategies were compared, which differed in the first cycle only: group A (n = 141) received eSET irrespective of the availability of a good-quality embryo, and group B (n = 174) received eSET when a good-quality embryo was available while otherwise they received double embryo transfer (DET; referred to as eSET/DET transfer policy). In any subsequent cycle, in both groups the eSET/DET transfer policy was applied.

Results: After completion of their IVF treatment (including a maximum of three fresh cycles and the transfer of frozen-thawed embryos), comparable cumulative live birth rates (62.4% in group A and 62.6% in group B) and twin pregnancy rates (10.1 versus 13.4%) were found. However, patients in group A required significantly more fresh (2.0 versus 1.8) and frozen (0.8 versus 0.5) cycles.

Conclusions: The transfer of one embryo in the first cycle, irrespective of the availability of a good-quality embryo, in all patients <38 years, is not an effective transfer policy for reducing the overall twin pregnancy rate.
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http://dx.doi.org/10.1093/humrep/dem059DOI Listing
June 2007

Single versus double embryo transfer: cost-effectiveness analysis alongside a randomized clinical trial.

Hum Reprod 2006 Aug 13;21(8):2090-7. Epub 2006 Apr 13.

Department of Clinical Epidemiology and Medical Technology Assessment, Academic Hospital Maastricht, The Netherlands.

Background: Twin pregnancies after IVF are still frequent and are considered high-risk pregnancies leading to high costs. Transferring one embryo can reduce the twin pregnancy rate. We compared cost-effectiveness of one fresh cycle elective single embryo transfer (eSET) versus one fresh cycle double embryo transfer (DET) in an unselected patient population.

Methods: Patients starting their first IVF cycle were randomized between eSET and DET. Societal costs per couple were determined empirically, from hormonal stimulation up to 42 weeks after embryo transfer. An incremental cost-effectiveness ratio (ICER) was calculated, representing additional costs per successful pregnancy.

Results: Successful pregnancy rates were 20.8% for eSET and 39.6% for DET. Societal costs per couple were significantly lower after eSET (7334 euro) compared with DET (10,924 euro). The ICER of DET compared with eSET was 19,096 euro, meaning that each additional successful pregnancy in the DET group will cost 19,096 euro extra.

Conclusions: One cycle eSET was less expensive, but also less effective compared to one cycle DET. It depends on the society's willingness to pay for one extra successful pregnancy, whether one cycle DET is preferred from a cost-effectiveness point of view.
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http://dx.doi.org/10.1093/humrep/del112DOI Listing
August 2006

In unselected patients, elective single embryo transfer prevents all multiples, but results in significantly lower pregnancy rates compared with double embryo transfer: a randomized controlled trial.

Hum Reprod 2006 Feb 27;21(2):338-43. Epub 2005 Oct 27.

Research Institute Growth & Development (GROW), Department of Obstetrics & Gynaecology, Academic Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands.

Background: Elective single embryo transfer (eSET) in a selected group of patients (i.e. young patients with at least one good quality embryo) reduces the number of multiple pregnancies in an IVF programme. However, the reduced overall multiple pregnancy rate (PR) is still unacceptably high. Therefore, a randomized controlled trial (RCT) was conducted comparing eSET and double embryo transfer (DET) in an unselected group of patients (i.e. irrespective of the woman's age or embryo quality).

Methods: Consenting unselected patients were randomized between eSET (RCT-eSET) (n = 154) or DET (RCT-DET) (n = 154). Randomization was performed just prior to the first embryo transfer, provided that at least two 2PN zygotes were available. Non-participants received our standard transfer policy [SP-eSET in a selected group of patients (n = 100), otherwise SP-DET (n = 122)].

Results: The ongoing PR after RCT-eSET was significantly lower as compared with RCT-DET (21.4 versus 40.3%) and the twin PR was reduced from 21.0% after RCT-DET to 0% after RCT-eSET. The ongoing PRs after SP-eSET and SP-DET did not differ significantly (33.0 versus 30.3%), with an overall twin PR of 12.9%.

Conclusion: To avoid twin pregnancies resulting from an IVF treatment, eSET should be applied in all patients. The consequence would be a halving of the ongoing PR as compared with applying a DET policy in all patients. The transfer of one embryo in a selected group of good prognosis patients leads to a less drastic reduction in PR but maintains a twin PR of 12.9%.
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http://dx.doi.org/10.1093/humrep/dei359DOI Listing
February 2006
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