Alarming increase in poisonings from recreational nitrous oxide use after a change in EU-legislation, inquiries to the Dutch Poisons Information Center.

BACKGROUND: After the change in EU-legislation in 2014, recreational use of nitrous oxide (N2O) increased in the Netherlands from 2015 onwards. We studied the effect on N2O poisonings during an 11 year period. METHODS: A retrospective observational study was performed on the incidence rate of N2O poisonings, relative to all recreational drug poisonings reported to the Dutch Poisons Information Center (DPIC) from 2010-2020. Secondary outcomes were the frequency of heavy use, frequent use, co-exposures, and toxicity in 2019 and 2020. RESULTS: 433 N2O poisonings were included. The incidence rate increased exponentially from 0.12% in 2010 to 11% in 2020, with an average monthly rate of 3.8%. In 2019 and 2020, 79% of the patients indicated heavy use, frequent use or both, and 42% used from large cylinders. Chronic toxicity (signs of peripheral neuropathy) was reported in 38% of the patients. CONCLUSION: The rate of N2O poisonings increased alarmingly in the Netherlands. An increasing proportion of patients reported problematic heavy or frequent use, accompanied by chronic toxicity.

Cost-effectiveness of 'immediate IVF' versus 'delayed IVF': a prospective study.

STUDY QUESTION: How does the cost-effectiveness (CE) of immediate IVF compared with postponing IVF for 1 year, depend on prognostic characteristics of the couple? SUMMARY ANSWER: The CE ratio, i.e. the incremental costs of immediate versus delayed IVF per extra live birth, is the highest (range of €15 000 to >€60 000) for couples with unexplained infertility and for them depends strongly on female age and the duration of infertility, whilst being lowest for endometriosis (range 8000-23 000) and, for such patients, only slightly dependent on female age and duration of infertility. WHAT IS KNOWN ALREADY: A few countries have guidelines for indications of IVF, using the diagnostic category, female age and duration of infertility. The CE of these guidelines is unknown and the evidence base exists only for bilateral tubal occlusion, not for the other diagnostic categories. STUDY DESIGN, SIZE, DURATION: A modelling approach was applied, based on the literature and data from a prospective cohort study among couples eligible for IVF or ICSI treatment, registered in a national waiting list in The Netherlands between January 2002 and December 2003. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 5962 couples was included. Chances of natural ongoing pregnancy were estimated from the waiting list observations and chances of ongoing pregnancy after IVF from follow-up data of couples with primary infertility that began treatment. Prognostic characteristics considered were female age, duration of infertility and diagnostic category. Costs of IVF were assessed from a societal perspective and determined on a representative sample of patients. A cost-effectiveness comparison was made between two scenarios: (I) wait one more year and then undergo IVF for 1 year and (II) immediate IVF during 1 year, and try to conceive naturally in the following year. Comparisons were made for strata determined by the prognostic factors. The final outcome was a live birth. MAIN RESULTS AND THE ROLE OF CHANCE: The gain in live birth rate of the immediate IVF scenario versus postponed IVF increased with female age, and was independent from diagnostic category or duration of infertility. By contrast, the corresponding increase in costs primarily depended on diagnostic category and duration of infertility. The lowest CE ratio was just below €10 000 per live birth for endometriosis from age 34 onwards at 1 year duration. The highest CE ratio reached €56 000 per live birth for unexplained infertility at age 30 and 3 years duration, dropping to values below € 30 000 per live birth from age 32 onwards. It reached values below €20 000 per live birth with 3 years duration at age 34 and older. The CE ratio was in between for the three other diagnostic categories (i.e. Male infertility, Hormonal and Immunological/Cervical). LIMITATIONS, REASONS FOR CAUTION: We applied estimates of chances with IVF, excluding frozen embryos, for which we had no data. Therefore, we do not know the effect of frozen embryo transfers on the CE. WIDER IMPLICATIONS OF THE FINDINGS: The duration of infertility at which IVF becomes cost-effective depends, firstly, on the level of society's willingness to pay for one extra live birth, and secondly, given a certain level of willingness to pay, on the woman's age and the diagnostic category. In current guidelines, the chances of a natural conception should always be taken into account before deciding whether to start IVF treatment and at which time. STUDY FUNDING/COMPETING INTEREST(S): Supported by Netherlands Organisation for Health Research and Development (ZonMW, grant 945-12-013). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none.

High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury.

PURPOSE: Lung transplant recipients often develop acute kidney injury (AKI) evolving into chronic kidney disease (CKD). The immunosuppressant tacrolimus might be associated with the emergence of AKI. We analyzed the development and recovery of kidney injury after lung transplantation and related AKI to whole-blood tacrolimus trough concentrations and other factors causing kidney injury. METHODS: We retrospectively studied kidney injury in 186 lung-transplantation patients at the UMC Utrecht between 2001 and 2011. Kidney function and whole-blood tacrolimus trough concentrations were determined from day 1 to 14 and at 1, 3, 6, and 12 months postoperative. Systemic inflammatory response syndrome (SIRS), septic shock, and nephrotoxic medications were evaluated as covariates for AKI. We analyzed liver injury and drug-drug interactions. RESULTS: AKI was present in 85 (46%) patients. Tacrolimus concentrations were supra-therapeutic in 135 of 186 patients (73%). AKI in the first week after transplantation was related to supra-therapeutic tacrolimus concentrations (OR 1.55; 95% CI 1.06-2.27), ≥3 other nephrotoxic drugs (OR 1.96; 95% CI 1.02-3.77), infection (OR 2.48; 95% CI 1.31-4.70), and cystic fibrosis (OR 2.17; 95% CI 1.16-4.06). Recovery rate of AKI was lower than expected (19%), and the cumulative incidence of severe CKD at 1 year was 15%. CONCLUSIONS: After lung transplantation, AKI is common and often evolves into severe CKD, which is a known cause of morbidity and mortality. Supra-therapeutic whole-blood tacrolimus trough concentrations are related to the early onset of AKI. Conscientious targeting tacrolimus blood concentrations might be vital in the early phase after lung transplantation. What is known about this subject? • Lung transplant recipients often develop acute kidney injury evolving into chronic kidney disease increasing both morbidity and mortality. • To date, the pathophysiology of kidney injury after lung transplantation has not been fully elucidated. • The immunosuppressant tacrolimus is difficult to dose, especially in the unstable clinical setting, and is nephrotoxic. WHAT THIS STUDY ADDS: • For the first time, supra-therapeutic whole-blood tacrolimus trough concentrations are related to the emergence of acute kidney injury in the first days after lung transplantation. • Supra-therapeutic whole-blood tacrolimus trough concentrations often occur early after lung transplantation. • AKI after lung transplantation shows low recovery rates.

Evaluation of three physiologically based pharmacokinetic (PBPK) modeling tools for emergency risk assessment after acute dichloromethane exposure.

INTRODUCTION: Physiologically based pharmacokinetic (PBPK) models may be useful in emergency risk assessment, after acute exposure to chemicals, such as dichloromethane (DCM). We evaluated the applicability of three PBPK models for human risk assessment following a single exposure to DCM: one model is specifically developed for DCM (Bos) and the two others are semi-generic ones (Mumtaz and Jongeneelen). MATERIALS AND METHODS: We assessed the accuracy of the models' predictions by simulating exposure data from a previous healthy volunteer study, in which six subjects had been exposed to DCM for 1h. The time-course of both the blood DCM concentration and percentage of carboxyhemoglobin (HbCO) were simulated. RESULTS: With all models, the shape of the simulated time course resembled the shape of the experimental data. For the end of the exposure, the predicted DCM blood concentration ranged between 1.52-4.19mg/L with the Bos model, 1.42-4.04mg/L with the Mumtaz model, and 1.81-4.31mg/L with the Jongeneelen model compared to 0.27-5.44mg/L in the experimental data. % HbCO could be predicted only with the Bos model. The maximum predicted % HbCO ranged between 3.1 and 4.2% compared to 0.4-2.3% in the experimental data. The % HbCO predictions were more in line with the experimental data after adjustment of the Bos model for the endogenous HbCO levels. CONCLUSIONS: The Bos Mumtaz and Jongeneelen PBPK models were able to simulate experimental DCM blood concentrations reasonably well. The Bos model appears to be useful for calculating HbCO concentrations in emergency risk assessment.

Review of acute chemical incidents as a first step in evaluating the usefulness of physiologically based pharmacokinetic models in such incidents.

CONTEXT. Acute chemical incidents can have substantial public health consequences in terms of morbidity and mortality. OBJECTIVE. We aimed to characterize acute chemical incidents and near-misses in the Netherlands and compare the results with previous studies. This review is a first step in evaluating whether Physiologically Based Pharmacokinetic (PBPK) models can be of value in acute chemical incidents. MATERIAL AND METHODS. Government, regional, municipal and University Hospital Institutes involved in the management of acute chemical incidents in the Netherlands were contacted, and they provided data between 2008 and 2010 on the characteristics and consequences of the incidents. The study is a retrospective epidemiological study based on data from five institutes. Incidents involving biological agents or radiation were excluded. RESULTS. A total of 764 reports were available which involved 722 incidents after cross-matching the different sources of data. Forty incidents were excluded, leaving 682 incidents for which information was available in accordance with the inclusion criteria. Of the 682 incidents included in this study, most occurred in non-industrial buildings (37%) or industrial sites (34%). The most frequently observed event types were loss of containment (60%) and fire (36%), leading to gas emission (54%), followed by spill of liquid or solid chemicals (36%). The chemicals involved were most often products of combustion (e.g. smoke, soot, particles, 25%) and volatile organic compounds (e.g. solvents, styrene, xylene, 23%), followed by inorganic gases (e.g. carbon monoxide, hydrogen, hydrogen sulphide, 13%). A minimum of 847 people experienced adverse health effects following exposure during a chemical incident, and 10 fatalities were reported. The most frequently reported symptoms were respiratory (27%), due to irritant chemicals. The number of incidents related to fire and the number of injured people were higher in this study than in previous studies; 49% of the injured were transported to hospital. DISCUSSION. This study helps to identify which chemicals are frequently involved in acute chemical incidents in the Netherlands. The results will be used in future to assess whether PBPK models may be useful for risk assessment of chemicals often involved in acute chemical incidents and for which human toxicological and kinetic data are scarce.

Cannabis with high δ9-THC contents affects perception and visual selective attention acutely: an event-related potential study.

OBJECTIVE: Cannabis intake has been reported to affect cognitive functions such as selective attention. This study addressed the effects of exposure to cannabis with up to 69.4mg Delta(9)-tetrahydrocannabinol (THC) on Event-Related Potentials (ERPs) recorded during a visual selective attention task. METHODS: Twenty-four participants smoked cannabis cigarettes with four doses of THC on four test days in a randomized, double blind, placebo-controlled, crossover study. Two hours after THC exposure the participants performed a visual selective attention task and concomitant ERPs were recorded. RESULTS: Accuracy decreased linearly and reaction times increased linearly with THC dose. However, performance measures and most of the ERP components related specifically to selective attention did not show significant dose effects. Only in relatively light cannabis users the Occipital Selection Negativity decreased linearly with dose. Furthermore, ERP components reflecting perceptual processing, as well as the P300 component, decreased in amplitude after THC exposure. Only the former effect showed a linear dose-response relation. CONCLUSIONS: The decrements in performance and ERP amplitudes induced by exposure to cannabis with high THC content resulted from a non-selective decrease in attentional or processing resources. SIGNIFICANCE: Performance requiring attentional resources, such as vehicle control, may be compromised several hours after smoking cannabis cigarettes containing high doses of THC, as presently available in Europe and Northern America.

Pregnancy chances on an IVF/ICSI waiting list: a national prospective cohort study.

BACKGROUND: The effectiveness of IVF over expectant management has been proven only for bilateral tubal occlusion. We aimed to estimate the chance of pregnancy without treatment for IVF patients, using data on the waiting period before the start of IVF. METHODS: A prospective cohort study included all couples eligible for IVF or ICSI treatment, registered in a national waiting list in The Netherlands. The cumulative probability of treatment-free ongoing pregnancy on the IVF waiting list was assessed and the predictive effect of female age, duration of infertility, primary or secondary infertility and diagnostic category was estimated using Cox regression. RESULTS: We included 5962 couples on the waiting list. The cumulative probability of treatment-free ongoing pregnancy was 9% at 12 months. In multivariable Cox regression, hazard ratios were: 0.95 (P < 0.001) per year of the woman's age, 0.85 (P < 0.001) per year of duration of infertility, 0.71 (P = 0.005) for primary versus secondary infertility. Diagnostic category showed hazard ratios of 0.7, 1.6, 1.2, 1.7 and 2.6 for endometriosis, male factor, hormonal, immunological and unexplained infertility, respectively, compared with 'tubal infertility' (P < 0.001). The 12-months predicted probabilities ranged from 0% to 25%. CONCLUSIONS: The chance of an ongoing pregnancy without treatment while waiting for an IVF or ICSI is below 10% but may be as high as 25% within 1 year for selected patient groups. Timing of IVF should take predictive factors into consideration.

Effects of sub-chronic nitrate exposure on the thyroidal function in humans.

No experimental data exist on the thyroid toxicity of nitrate among humans. We aimed to show that no significant antithyroid effect could be observed after exposure to a three times the acceptable daily intake of nitrate in humans. In a randomized controlled non-inferiority trial, 10 volunteers received 15 mg/kg sodium nitrate during 28 days whereas 10 control participants received distilled water. We performed 5- and 24-h measurements of thyroidal (131)I uptake (RAIU) before and at the end of the exposure period. Thyroid hormone plasma concentrations of T3, rT3, T4, TSH were also measured prior to and after exposure. Differences in RAIU between the intervention and the control groups at 4 weeks were 3.4% (95% confidence interval -0.5 to 7.3, and 4.8% (95% confidence interval -1.4 to 11.0, respectively, for the 5- and 24-h RAIU measurement. Plasma concentrations of thyroid hormones stayed normal. In conclusion, no significant effects on thyroidal (131)I uptake and thyroid hormones plasma concentrations were observed after sub-chronic exposition to 15 mg/kg sodium nitrate among humans.

Predicting ongoing pregnancy chances after IVF and ICSI: a national prospective study.

BACKGROUND: The Dutch IVF guideline suggests triage of patients for IVF based on diagnostic category, duration of infertility and female age. There is no evidence for the effectiveness of these criteria. We evaluated the predictive value of patient characteristics that are used in the Dutch IVF guideline and developed a model that predicts the IVF ongoing pregnancy chance within 12 months. METHODS: In a national prospective cohort study, pregnancy chances after IVF and ICSI treatment were assessed. Couples eligible for IVF or ICSI were followed during 12 months, using the databases of 11 IVF centres and 20 transport IVF clinics. Kaplan-Meier analysis was performed to estimate the cumulative probability of an ongoing pregnancy, and Cox regression was used for assessing the effects of predictors of pregnancy. RESULTS: 4928 couples starting IVF/ICSI treatment were prospectively followed. On average, couples had 1.8 cycles in 12 months for both IVF and ICSI. The 1-year probability of ongoing pregnancy was 44.8% (95% CI 42.1-47.5%). ICSI for severe oligospermia had a significantly higher ongoing pregnancy rate than IVF indicated treatments, with a multivariate Hazard ratio (HR) of 1.22 (95% CI 1.07-1.39). The success rates were comparable for all diagnostic categories of IVF. The highest success rate is at age 30, with a slight decline towards younger women and women up to 35 and a sharp drop after 35. Primary subfertility with a HR of 0.90 (95% CI 0.83-0.99) and duration of subfertility with a HR of 0.97 (95% CI 0.95-0.99) per year significantly affected the pregnancy chance. CONCLUSIONS: The most important predictors of the pregnancy chance after IVF and ICSI are women's age and ICSI. The diagnostic category is of no consequence. Duration of subfertility and pregnancy history are of limited prognostic value.

Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models.

BACKGROUND: Several models have been published for the prediction of spontaneous pregnancy among subfertile patients. The aim of this study was to broaden the empirical basis for these predictions by making a synthesis of three previously published models. METHODS: We used the original data from the studies of Eimers et al. (1994), Collins et al. (1995) and Snick et al. (1997) on couples consulting for various forms of subfertility. We developed a so-called three-sample synthesis model for predicting spontaneous conception leading to live birth within 1 year after intake based on the three data sets. The predictors used are duration of subfertility, women's age, primary or secondary infertility, percentage of motile sperm, and whether the couple was referred by a general practitioner or by a gynaecologist (referral status). The performance of this model was assessed according to a 'jack-knife' analysis. Because the post-coital test (PCT) was not assessed in one of the samples, a synthesis model including the PCT was based on two samples only. RESULTS: The ability of the synthesis models to distinguish between women who became pregnant and those who did not was comparable to the ability of the one-sample models when applied in the other samples. The reliability of the predictions by the three-sample synthesis model was somewhat better. Predictions improved considerably by including the PCT. CONCLUSIONS: The synthesis models performed better and had a broader empirical basis than the original models. They are therefore better suitable for application in other centres.