Updating Clinical Prediction Models: An Illustrative Case Study.

The performance of clinical prediction models tends to deteriorate over time. Researchers often develop a new prediction if an existing model performs poorly at external validation. Model updating is an efficient technique and promising alternative to the de novo development of clinical prediction models. Model updating has been recommended by the TRIPOD guidelines. To illustrate several model updating techniques, a case study is provided for the development and updating of a clinical prediction model assessing postoperative anxiety in data coming from two double-blinded placebo-controlled randomized controlled trials with a very similar methodological framework. Note that the developed model and updated model are for didactic purposes only. This paper discusses some common considerations and caveats for researchers to be aware of when planning or applying updating of a prediction model.

The effect of midazolam as premedication on the quality of postoperative recovery after laparotomy: a randomized clinical trial.

PURPOSE: Despite the uncertain effects of anxiolytic premedication with benzodiazepines on the quality of postoperative recovery, perioperative benzodiazepine administration is still a common practice in many hospitals. We evaluated the effect of premedication with midazolam on the quality of recovery in hospitalized patients undergoing a laparotomy. METHODS: We conducted a single-centre randomized placebo-controlled, double-blinded clinical trial from July 2014 to September 2015. We included 192 patients aged > 18 yr scheduled for elective laparotomy with a planned postoperative stay of ≥ three days. Participants were randomized into two groups to receive either midazolam 3 mg or sodium chloride 0.9% intravenously as premedication prior to surgery. Patients were followed up for up to one week after surgery. The primary outcome was the Quality of Recovery-40 (QoR-40) score on postoperative day (POD) 3. The secondary outcomes included the QoR-40 score on POD 7, and the State-Trait Anxiety Inventory, State-Trait Anger Scale, Multidimensional Fatigue Inventory, and the Hospital Anxiety and Depression Scale scores. RESULTS: The mean (standard deviation) postoperative QoR-40 scores on POD 3 were not significantly different in the midazolam group compared with controls [166.4 (17.0) vs 163.9 (19.8), respectively; mean difference, 2.3; 95% confidence interval, - 2.9 to 8.4; P = 0.35]. There were no between-group differences in any of the secondary outcomes. CONCLUSIONS: Administration of midazolam as premedication for laparotomy patients did not improve the quality of recovery up to one week after surgery. General prescription of midazolam as premedication can be questioned and might only suit some patients. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01993459); registered 29 October, 2013.

Implication of UGT2B15 Genotype Polymorphism on Postoperative Anxiety Levels in Patients Receiving Lorazepam Premedication.

BACKGROUND: Lorazepam is used as premedication for its anxiolytic properties. The UGT2B15 genotype is of importance for the metabolism of lorazepam. The clinical effect of genetic polymorphisms in UGT2B15 genotype on the treatment of anxiety levels in same-day surgery patients receiving lorazepam, however, is unknown. METHODS: Three hundred ninety-eight same-day surgery patients of mixed sex (from a previous double-blinded randomized controlled trial who were assigned to either lorazepam [n = 198] or placebo [n = 200]) were assessed for the UGT2B15*2 variant allele. Anxiety was measured preoperatively and postoperatively by the State part of the State-Trait Anxiety Inventory. The difference between these 2 measurements served as outcome of the study. Analysis of variance was used to assess the State part of the State-Trait Anxiety Inventory difference for interactions among the following factors: UGT2B15 genotype status, treatment condition (lorazepam or placebo), patient sex, and preoperative anxiety score. RESULTS: The anxiety difference was complex in that the interaction of lorazepam and UGT2B15 genotype status also was dependent on the joint effect of patient sex and preoperative anxiety score (F = 7.15, P = .008). Further exploration showed clinical relevant results in patients with high preoperative anxiety scores. Striking was that females with high preoperative anxiety scores and genetically reduced lorazepam glucuronidation (UGT2B15*2 homozygotes) showed more postoperative anxiety reduction than males with the same genotype. CONCLUSIONS: UGT2B15 genotype contributes to postoperative anxiety reduction after lorazepam premedication. Future research that focuses on patients with high preoperative anxiety scores could help to gain a deeper understanding in the clinical relevance of the interaction between lorazepam and UGT2B15 genotype on postoperative anxiety levels.

Development and external validation of a clinical prediction model for predicting quality of recovery up to 1 week after surgery.

The Quality of Recovery Score-40 (QoR-40) has been increasingly used for assessing recovery after patients undergoing surgery. However, a prediction model estimating quality of recovery is lacking. The aim of the present study was to develop and externally validate a clinical prediction model that predicts quality of recovery up to one week after surgery. The modelling procedure consisted of two models of increasing complexity (basic and full model). To assess the internal validity of the developed model, bootstrapping (1000 times) was applied. At external validation, the model performance was evaluated according to measures for overall model performance (explained variance (R2)) and calibration (calibration plot and slope). The full model consisted of age, sex, previous surgery, BMI, ASA classification, duration of surgery, HADS and preoperative QoR-40 score. At model development, the R2 of the full model was 0.24. At external validation the R2 dropped as expected. The calibration analysis showed that the QoR-40 predictions provided by the developed prediction models are reliable. The presented models can be used as a starting point for future updating in prediction studies. When the predictive performance is improved it could be implemented clinically in the future.

Lorazepam does not improve the quality of recovery in day-case surgery patients: a randomised placebo-controlled clinical trial.

BACKGROUND: In day-case surgery, the effects of the anxiolytic lorazepam as premedication on the quality of postoperative recovery are unknown. OBJECTIVE: To evaluate whether lorazepam as a premedication beneficially affects quality of recovery (primary outcome) and psychological manifestations (secondary outcome) after day-case surgery. DESIGN: A randomised, double-blind, placebo-controlled clinical trial. SETTING: Single tertiary centre. INCLUSION CRITERIA: day-case surgery; age at least 18 years. EXCLUSION CRITERIA: insufficient knowledge of the Dutch language; intellectual disability; ophthalmology surgery; extracorporeal shock wave lithotripsy; endoscopy; botulinum toxin A treatment; abortion; chronic pain treatment; preceding use of psychopharmaceuticals; contraindication to lorazepam. INTERVENTION: Lorazepam (1 to 1.5 mg) intravenously vs. NaCl 0.9% as a premedication prior to surgery. MAIN OUTCOME MEASURE: Quality of Recovery-40 (QoR-40) score. SECONDARY OUTCOMES: State-Trait Anxiety Inventory (STAI-State/Trait); State-Trait Anger Scale (STAS-State/Trait); Multidimensional Fatigue Inventory (MFI); Hospital Anxiety and Depression Scale (HADS). Timing of evaluation: T0: preoperatively (all scales); T1: before discharge (STAI-State/Trait); T2: first postoperative working day (QoR-40); T3: 7th day after surgery (all scales). Robust regression analysis was applied. Statistical analyses were adjusted for the corresponding baseline value and sex. RESULTS: Four hundred patients were randomised; 398 patients were analysed. Postoperative mean QoR-40 scores were similar in both groups at T2 (174.5 vs. 176.4, P = 0.34) and T3 (172.8 vs.176.3, P = 0.38). Postoperative mean STAI-State/Trait scores decreased less in the group with lorazepam at T1 (32.3 vs. 29.3, P < 0.0001; 32.7 vs. 30.8, P = 0.0002). STAI-Trait and HADS-Anxiety decreased less in the group with lorazepam at T3 (31.1 vs. 30.0; P = 0.03, 3.3 vs. 2.5, P = 0.003). STAS-State increased in the group with lorazepam at T3 (10.8 vs. 10.3, P = 0.04). CONCLUSION: In day-case surgery, lorazepam as a premedication did not improve quality of recovery. Furthermore, this premedication may delay the decrease in postoperative anxiety and aggression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01441843.

Potential neurotoxicity of anesthetic drugs in young children: who cares? A survey among European anesthetists.

BACKGROUND: Potential neurotoxicity of anesthetic drugs is currently one of the most intensely discussed issues in pediatric anesthesia. Prospective human data are sorely lacking and there is an on-going debate among experts in the field whether one should (or can) extrapolate animal data to humans. Data regarding the thoughts of practicing anesthetists regarding this topic have not been published. METHODS: A web-based survey to assess the thoughts of practicing (European) anesthetists regarding neurotoxicity and how it may have influenced their daily practice of pediatric anesthesia. RESULTS: The majority (68.7%) of respondents regard neurotoxicity as an important topic, which they need to further explore. Two thirds have already changed their clinical practice and 44.3% were concerned about potential neurotoxicity. Anesthetists from children's hospitals were less likely to routinely inform parents about neurotoxicity (P=0.005) and more often applied an opioid-only anesthesia technique in selected premature neonates than general hospital based anesthetists (P<0.0001). Prospective human longitudinal studies focusing on neurodevelopment were given the highest priority for future research, whereas animal studies scored lowest. CONCLUSIONS: Practicing anesthetists care about potential neurotoxicity of anesthetic drugs in young children. Colleagues working in children's hospital have slightly different attitudes to deal with the topic, compared to those working in general hospitals. The vast majority of our colleagues are waiting for prospective human research data that may help to unravel the current controversy surrounding potential anesthetic drug neurotoxicity and help to improve the safety of pediatric anesthesia.

Effectiveness of benzodiazepine premedication on recovery in day-case surgery: a systematic review with meta-analysis.

INTRODUCTION: Benzodiazepines are frequently used as a premedication. In day-case surgery, anesthetists are reluctant to administer benzodiazepines preoperatively for reasons of delayed recovery. However, premedication with benzodiazepines might be beneficial regarding postoperative somatic symptoms/complaints (i.e. time to recovery and postoperative side effects) and psychological phenomena. EVIDENCE ACQUISITION: A systematic review with meta-analysis was performed using all important search engines. Study methodological quality was assessed using risk of bias tables. Mean differences (MD) and odds ratios (OR) were used for continuous data (time to recovery and psychological phenomena) and categorical data (postoperative somatic symptoms) respectively. Random effects modelling was applied. Nineteen studies were included. Overall time to recovery was significantly delayed in patients receiving benzodiazepines (MD 1.75; 95% CI 0.82 to 2.69) although time to discharge was not significantly affected. Postoperative side effects were significantly reduced in patients receiving benzodiazepines (OR 0.47; 95% CI 0.36 to 0.63). Regarding psychological outcome, only anxiety could be statistically analyzed showing no statistical difference (MD 1.47; 95% CI -1.01 to 3.96). EVIDENCE SYNTHESIS: Although overall time to recovery was significantly prolonged by benzodiazepine premedication, withholding premedication in day-case surgery patients is not justified for such reason, as time to discharge was not negatively affected. Furthermore, benzodiazepines show to have beneficial effects on postoperative side effects. CONCLUSIONS: For a firm conclusion regarding psychological phenomena, more research is needed. Anaesthetists should take into account this new evidence when they apply their premedication regime in day-case surgery.