Semen analysis and reproductive hormones in boys with classical Hodgkin lymphoma treated according to the EuroNet-PHL-C2 protocol.

STUDY QUESTION: What is the impact of the EuroNet-PHL-C2 treatment for boys with classical Hodgkin lymphoma (cHL) on semen parameters? SUMMARY ANSWER: More than half of the patients (52%, n = 16/31) had oligozoospermia or azoospermia at 2 years from cHL diagnosis; particularly boys treated for advanced-stage cHL had low sperm counts and motility. WHAT IS KNOWN ALREADY: Chemotherapy and radiotherapy to the inguinal region or testes can impair spermatogenesis and result in reduced fertility. The EuroNet-PHL-C2 trial aims to minimize radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. The present study aims to assess the (gonadotoxic) impact of this treatment protocol on semen parameters and reproductive hormones in boys aged ≤18 years. STUDY DESIGN, SIZE, DURATION: This international, prospective, multi-centre cohort study was an add-on study to the randomized phase-3 EuroNet-PHL-C2 trial, where the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) was compared to intensified OEPA-DECOPDAC-21 chemotherapy (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide). Patients were recruited between January 2017 and September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligibility criteria included male patients, diagnosed with classical HL before or at the age of 18 years, and treated according to the EuroNet-PHL-C2 protocol in any of the 18 participating sites in the Netherlands, Germany, Belgium, Czech Republic, and Austria. Sperm parameters (sperm concentration, progressive motility, sperm volume, and calculated total motile sperm count) were assessed at diagnosis and 2 years after diagnosis in (post)pubertal boys. Laboratory measurements (serum follicle-stimulating hormone (FSH) and inhibin B) were performed in samples drawn at diagnosis, during treatment (2-3 times), and at 2 years post-diagnosis, and (age-adjusted) analyses were conducted separately for pre-pubertal and (post)pubertal boys. Outcomes were compared between the treatment levels (TL1, TL2, and TL3) and consolidation treatment schemes (COPDAC-28 and DECOPDAC-21). MAIN RESULTS AND THE ROLE OF CHANCE: In total, 101 boys were included in the present analysis: 73 were (post)pubertal (median age 15.4 years, (IQR 14.4; 16.6), 10 TL1, 29 TL2, 34 TL3, 62% of TL2/3 patients received COPDAC-28) and 28 boys were pre-pubertal (median age 9.6 years (IQR 6.6; 11.4), 4 TL1, 7 TL2, 17 TL3, 38% of TL2/3 patients received COPDAC-28). The study included six boys who had received pelvic radiotherapy; none were irradiated in the inguinal or testicular area. At diagnosis, 48 (post)pubertal boys delivered semen for cryopreservation; 19 (40%) semen samples were oligospermic and 4 (8%) were azoospermic. Low sperm concentration (<15 mil/ml) appeared to be related to the HL disease itself, with a higher prevalence in boys who presented with B symptoms (76% vs 26%, aOR 2.3 (95% CI 1.0; 3.8), P = 0.001) compared to those without such symptoms. At 2 -years post-diagnosis, 31 boys provided semen samples for analysis, of whom 12 (39%) boys had oligozoospermia and 4 (13%) had azoospermia, while 22 boys (71%) had low total motile sperm counts (TMSC) (<20 mil). Specifically, the eight boys in the TL3 group treated with DECOPDAC-21 consolidation had low sperm counts and low progressive motility after 2 years (i.e. median sperm count 1.4 mil/ml (IQR <0.1; 5.3), n = 7 (88%), low sperm concentration, low median progressive motility 16.5% (IQR 0.0; 51.2), respectively). Age-adjusted serum FSH levels were significantly raised and inhibin B levels (and inhibin B:FSH ratios) were decreased during chemotherapy in (post)pubertal boys, with subsequent normalization in 80% (for FSH) and 60% (for inhibin B) of boys after 2 years. Only 4 out of the 14 (post)pubertal boys (29%) with low sperm concentrations after 2 years had elevated FSH (>7.6 IU/l), while 7 (50%) had low inhibin B levels (<100 ng/l). In pre-pubertal boys, reproductive hormones were low overall and remained relatively stable during chemotherapy. LIMITATIONS, REASONS FOR CAUTION: The present analyses included sperm and laboratory measurements up to 2 years post-diagnosis. Long-term reproductive outcomes and potential recovery of spermatogenesis remain unknown, while recovery was reported up to 5- or even 10-year post-chemotherapy in previous studies.Boys who were pre-pubertal at diagnosis were still too young and/or physically not able to deliver semen after 2 years and we could not assess a potential difference in gonadotoxicity according to pubertal state at the time of treatment. Overall, the statistical power of the analyses on sperm concentration and quality after 2 years was limited. WIDER IMPLICATIONS OF THE FINDINGS: Results of the semen analyses conducted among the 31 boys who had provided a semen sample at 2 years post-treatment were generally poor. However, additional long-term and adequately powered data are crucial to assess the potential recovery and clinical impact on fertility. The participating boys will be invited to deliver a semen sample after 5 years. Until these data become available, benefits of intensified chemotherapy in cHL treatment to reduce radiotherapy and lower risk for development of secondary tumours should be carefully weighed against potentially increased risk of other late effects, such as diminished fertility due to the increased chemotherapy burden. Boys with newly diagnosed cHL should be encouraged to deliver sperm for cryopreservation whenever possible. However, patients and clinicians should also realize that the overall state of disease and inflammatory milieu of cHL can negatively affect sperm quality and thereby reduce chance of successful fertility preservation. Furthermore, the measurement of FSH and inhibin B appears to be of low value in predicting low sperm quality at two years from cHL treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M.-K., D.K., W.H.W., D.H., MC, A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors declare no potential conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The impact of treatment for childhood classical Hodgkin lymphoma according to the EuroNet-PHL-C2 protocol on serum anti-Müllerian Hormone.

STUDY QUESTION: What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)? SUMMARY ANSWER: Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL. WHAT IS KNOWN ALREADY: Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol. STUDY DESIGN, SIZE, DURATION: This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years. LIMITATIONS, REASONS FOR CAUTION: The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2-5 years post-diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol. STUDY FUNDING/COMPETING INTEREST(S): The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K., D.K., W.H.W., D.H., M.C., A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Advanced waveform analysis of diaphragm surface EMG allows for continuous non-invasive assessment of respiratory effort in critically ill patients at different PEEP levels.

BACKGROUND: Respiratory effort should be closely monitored in mechanically ventilated ICU patients to avoid both overassistance and underassistance. Surface electromyography of the diaphragm (sEMGdi) offers a continuous and non-invasive modality to assess respiratory effort based on neuromuscular coupling (NMCdi). The sEMGdi derived electrical activity of the diaphragm (sEAdi) is prone to distortion by crosstalk from other muscles including the heart, hindering its widespread use in clinical practice. We developed an advanced analysis as well as quality criteria for sEAdi waveforms and investigated the effects of clinically relevant levels of PEEP on non-invasive NMCdi. METHODS: NMCdi was derived by dividing end-expiratory occlusion pressure (Pocc) by sEAdi, based on three consecutive Pocc manoeuvres at four incremental (+ 2 cmH2O/step) PEEP levels in stable ICU patients on pressure support ventilation. Pocc and sEAdi quality was assessed by applying a novel, automated advanced signal analysis, based on tolerant and strict cut-off criteria, and excluding inadequate waveforms. The coefficient of variations (CoV) of NMCdi after basic manual and automated advanced quality assessment were evaluated, as well as the effect of an incremental PEEP trial on NMCdi. RESULTS: 593 manoeuvres were obtained from 42 PEEP trials in 17 ICU patients. Waveform exclusion was primarily based on low sEAdi signal-to-noise ratio (Ntolerant = 155, 37%, Nstrict = 241, 51% waveforms excluded), irregular or abrupt cessation of Pocc (Ntolerant = 145, 35%, Nstrict = 145, 31%), and high sEAdi area under the baseline (Ntolerant = 94, 23%, Nstrict = 79, 17%). Strict automated assessment allowed to reduce CoV of NMCdi to 15% from 37% for basic quality assessment. As PEEP was increased, NMCdi decreased significantly by 4.9 percentage point per cmH2O. CONCLUSION: Advanced signal analysis of both Pocc and sEAdi greatly facilitates automated and well-defined identification of high-quality waveforms. In the critically ill, this approach allowed to demonstrate a dynamic NMCdi (Pocc/sEAdi) decrease upon PEEP increments, emphasising that sEAdi-based assessment of respiratory effort should be related to PEEP dependent diaphragm function. This novel, non-invasive methodology forms an important methodological foundation for more robust, continuous, and comprehensive assessment of respiratory effort at the bedside.

Infarct-related chronic total coronary occlusion and the risk of ventricular tachyarrhythmic events in out-of-hospital cardiac arrest survivors.

INTRODUCTION: Chronic total coronary occlusion (CTO) has been identified as a risk factor for ventricular arrhythmias, especially a CTO in an infarct-related artery (IRA). This study aimed to evaluate the effect of an IRA-CTO on the occurrence of ventricular tachyarrhythmic events (VTEs) in out-of-hospital cardiac arrest survivors without ST-segment elevation. METHODS: We conducted a post hoc analysis of the COACT trial, a multicentre randomised controlled trial. Patients were included when they survived index hospitalisation after cardiac arrest and demonstrated coronary artery disease on coronary angiography. The primary endpoint was the occurrence of a VTE, defined as appropriate implantable cardioverter-defibrillator (ICD) therapy, sustained ventricular tachyarrhythmia or sudden cardiac death. RESULTS: A total of 163 patients from ten centres were included. Unrevascularised IRA-CTO in a main vessel was present in 43 patients (26%). Overall, 61% of the study population received an ICD for secondary prevention. During a follow-up of 1 year, 12 patients (7.4%) experienced at least one VTE. The cumulative incidence rate of VTEs was higher in patients with an IRA-CTO compared to patients without an IRA-CTO (17.4% vs 5.6%, log-rank p = 0.03). However, multivariable analysis only identified left ventricular ejection fraction < 35% as an independent factor associated with VTEs (adjusted hazard ratio 8.7, 95% confidence interval 2.2-35.4). A subanalysis focusing on CTO, with or without an infarct in the CTO territory, did not change the results. CONCLUSION: In out-of-hospital cardiac arrest survivors with coronary artery disease without ST-segment elevation, an IRA-CTO was not an independent factor associated with VTEs in the 1st year after the index event.

Quality of life after bone sarcoma surgery around the knee: A long-term follow-up study.

It remains unclear if quality of life (QoL) improvements could be expected in young patients after malignant bone tumour surgery after 2 years. To assess the course of QoL over time during a long-term follow-up, malignant bone tumour survivors of a previous short-term study were included. Assessments were done at least 5 years after surgery. QoL was measured with Short-form (SF)-36, TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL) and Bone tumour (Bt)-DUX. QoL throughout the follow-up was analysed by linear mixed model analysis. From the original cohort of 44 patients; 20 patients were included for this study, 10 males; mean age at surgery 15.1 years and mean follow-up 7.2 years. Twenty-one patients of the initial cohort (47%) deceased. Fifteen patients (75%) underwent limb-salvage and five (25%) ablative surgery. QoL improved significantly during follow-up at Physical Component Summary Scale scale of the SF-36 and TAAQOL and all subscales of the Bt-DUX (p < .01). No significant differences were found between current evaluations and previous evaluations at 2 years after surgery (p = .41-.98). Significant advantages after limb-salvage were seen at the PCS scale of the SF-36 (MD 13.7, p = .05) and the cosmetic scale of the Bt-DUX (MD 17.7, p = .04).

A prospective multicenter evaluation of direct molecular detection of blood stream infection from a clinical perspective.

BACKGROUND: Rapid diagnosis and appropriate antimicrobial therapy are of major importance to decrease morbidity and mortality in patients with blood stream infections (BSI). Blood culture, the current gold standard for detecting bacteria in blood, requires at least 24-48 hours and has limited sensitivity if obtained during antibiotic treatment of the patient. The aim of this prospective multicenter study was to clinically evaluate the application of a commercial universal 16S/18S rDNA PCR, SepsiTest™ (PCR-ST), directly on whole blood. METHODS: In total 236 samples from 166 patients with suspected sepsis were included in the study. PCR-ST results were compared to blood culture, the current gold standard for detecting BSI. Because blood cultures can give false-negative results, we performed an additional analysis to interpret the likelihood of bloodstream infection by using an evaluation based on clinical diagnosis, other diagnostic tests and laboratory parameters. RESULTS: Clinical interpretation of results defined the detected organism to be contaminants in 22 of 43 positive blood cultures (51.2 %) and 21 of 47 positive PCR-ST results (44.7 %). Excluding these contaminants resulted in an overall sensitivity and specificity of the PCR-ST of 66.7 and 94.4 % respectively. Of the 36 clinically relevant samples, 11 BSI were detected with both techniques, 15 BSI were detected with PCR-ST only and 10 with blood culture only. Therefore, in this study, SepsiTest™ detected an additional 71 % BSI compared to blood culture alone. CONCLUSIONS: More clinically relevant BSI were diagnosed by molecular detection, which might influence patient treatment. An improved SepsiTest™ assay suited for routine use can have additional value to blood culture in diagnosing bacteremia in septic patients.

Endocrine late sequelae in long-term survivors of childhood non-Hodgkin lymphoma.

BACKGROUND: Aim of this study was to investigate the long-term endocrine effects of treatment of childhood non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: A single-center cohort of 84 survivors (22 females) was included in this retrospective study. Median age was 21 years (9-40 years) and time after cessation of therapy 12 years (4-30 years). Height, weight, percentage fat, lean body mass (LBM), bone mineral content (BMC), bone mineral density of total body (BMD(TB)) and bone mineral density of lumbar spine (BMD(LS)) were measured. Thyroid-stimulating hormone (TSH), free thyroxin (fT4), insulin-like growth factor-1 (IGF-1), inhibin B and anti-müllerian hormone (AMH) levels were measured. Results were compared with Dutch controls. RESULTS: Height was lower in survivors [mean standard deviation score (SDS) -0.36, P = 0.002], but further analysis showed that shorter stature was already present at diagnosis (mean SDS -0.28, P = 0.023). Body mass index, percentage fat, BMC, BMD(TB) and BMD(LS) were not different from controls. LBM was lower in survivors (mean SDS -0.47, P = 0.008). TSH, fT4 and IGF-1 were normal in all survivors. Three of 20 adult females had low AMH levels and 23 of 42 adult males had low inhibin B levels. CONCLUSIONS: Twelve years after cessation of treatment, NHL survivors did not develop adiposity, osteoporosis or thyroid disease. Male survivors may be at risk for infertility.

The group medical appointment (GMA) in haemophilia and von Willebrand's disease: a new development in outpatient paediatric care.

The Group Medical Appointment (GMA) is a novel consultation form in which patients undergo individual consultations in each other's presence. To compare participants' experiences with GMA and Individual Medical Appointments (IMA), the usual standard of care, our team recently implemented the GMA for children aged 0-18 years with haemophilia or von Willebrand's disease. Participants' experiences with GMA were measured using a standardized QUOTE-questionnaire. Of 100 addressed families, 53 participated in GMA. Of these 53 families, 38 parents (72%) and 14 adolescents (82%) filled in the questionnaire about the GMA. Patients not on prophylaxis were defined as less experienced and patients on prophylaxis, as experienced. Although parents were satisfied with both GMA and IMA (median score 8.0 vs. 9.0 of 10), a significant difference was demonstrated between less experienced and experienced parents. After GMA, less experienced parents were significantly more satisfied (median score 8.0 vs. 5.0; P-value 0.006), felt more social support (82% vs. 30%; P-value 0.005) and reported additional learning effects with regard to disease and treatment (64% vs. 0%; P-value <0.001) than experienced parents. None of the less experienced parents reported privacy problems during GMA compared with 40% of experienced parents. In adolescents an identical trend was reported. Sixty-six per cent of parents would join a GMA in the future and 87% would recommend a GMA to others. The GMA is a valuable addition in haemophilia and von Willebrand care, especially for less experienced patients. It leads to improved satisfaction, social support and improved information.

[Intermediate-high risk pulmonary embolism: identification and treatment]. / Longembolie met intermediair-hoog risico op overlijden.

Patients with intermediate-high risk pulmonary embolism have a different mix of clinical symptoms. Optimal treatment of patients with intermediate high-risk pulmonary embolism is necessary to prevent short-term mortality. According to the current guidelines, the use of standard coagulation is the treatment of choice in hemodynamic stable patients with intermediate-high risk pulmonary embolism. Systemic thrombolytic therapy is recommended in patients with intermediate-high risk pulmonary embolism who circulatory deteriorate or who did not respond appropriately to standard anticoagulation. Catheter-guided thrombolysis is reserved for patients with intermediate-high risk pulmonary embolism who have a contraindication for systemic thrombolysis or did not respond to systemic thrombolysis. The timing and choice for the right treatment are significant treatment dilemmas. The development of pulmonary embolism response teams helps in the decision-making in patients with intermediate high-risk pulmonary embolism.

Routine reporting of grey-white matter differentiation in early brain computed tomography in comatose patients after cardiac arrest: A substudy of the COACT trial.

AIM: A multimodal approach is advised for neurological prognostication in comatose patients after out-of-hospital cardiac arrest (OHCA). Grey-white matter differentiation (grey-white ratio, GWR) obtained from a brain CT scan performed < 24 hours after return of circulation can be part of this approach. The aims of this study were to investigate the frequency and method of reporting the GWR in brain CT scan reports and their association with outcome. METHODS: This is a post-hoc descriptive analysis of the COACT trial. The primary endpoint was the reporting of GWR by the radiologist. Secondary endpoints were APACHE IV score, Cerebral Performance Categories at discharge and 90-day follow-up, Glasgow Coma Scale at discharge, GWR-stratified 1-year survival, and RAND-36 stratified by normal versus abnormal GWR. Associations were analysed using multivariable analysis. RESULTS: A total of 427 OHCA patients were included in this study, 234 (55%) of whom underwent a brain CT scan within 24 hours after ROSC. Median time between arrest and initial CT scan was 12 hours. In 195 patients (83%), the GWR was described in the reports, but always expressed qualitatively. The GWR was deemed abnormal in 57 (29%) CT scans. No differences were found in secondary endpoints between the two groups. CONCLUSION: GWR was frequently described in CT scan reports. Early abnormal GWR, as assessed qualitatively by a radiologist within 24 hours after ROSC, was a poor predictor of neurological prognosis.

Communicating with child patients in pediatric oncology consultations: a vignette study on child patients', parents', and survivors' communication preferences.

OBJECTIVE: To investigate the preferences of children with cancer, their parents, and survivors of childhood cancer regarding medical communication with child patients and variables associated with these preferences. METHODS: Preferences regarding health-care provider empathy in consultations, and children's involvement in information exchange and medical decision making were investigated by means of vignettes. Vignettes are brief descriptions of hypothetical situations, in which important factors are systematically varied following an experimental design. In total, 1440 vignettes were evaluated by 34 children with cancer (aged 8-16), 59 parents, and 51 survivors (aged 8-16 at diagnosis, currently aged 10-30). Recruitment of participants took place in three Dutch university-based pediatric oncology centers. Data were analyzed by multilevel analyses. RESULTS: Patients, parents, and survivors indicated the importance of health-care providers' empathy in 81% of the described situations. In most situations (70%), the three respondent groups preferred information about illness and treatment to be given to patients and parents simultaneously. Preferences regarding the amount of information provided to patients varied. The preference whether or not to shield patients from information was mainly associated with patients' age and emotionality. In most situations (71%), the three respondent groups preferred children to participate in medical decision making. This preference was mainly associated with patients' age. CONCLUSIONS: To be able to adapt communication to parents' and patients' preferences, health-care providers should repeatedly assess the preferences of both groups. Future studies should investigate how health-care providers balance their communication between the sometimes conflicting preferences of patients and parents.

Assessment of small bowel function in critical illness: potential role of citrulline metabolism.

Small intestinal function in critically ill patients should ideally be assessed in order to determine the preferred feeding route, timing, and composition of enteral nutrition. Additionally, evaluation of small bowel function may lead to new insights aimed to maintain enterocyte integrity. Critically ill patients are likely to have impaired enterocyte function mainly as a consequence of diminished splanchnic blood flow associated with mucosal hyperpermeability and bacterial translocation, a pathological state believed to be pivotal in the development of sepsis and multiple organ dysfunction syndrome (MODS). However, feasible and validated clinical tools to reliably assess enterocyte function are lacking. This explorative review discusses the promising role of citrulline, a nonprotein amino acid almost exclusively generated by the enterocyte, as a biomarker reflecting enterocyte function in critically ill patients. Citrulline metabolism, its potential as enterocyte biomarker, and literature on citrulline in critically illness will be discussed. Finally, a novel test for enterocyte function, the citrulline generation test (enterocytic citrulline production upon stimulation with enteral or intravenous glutamine) will be considered briefly.

Clinically relevant potential drug-drug interactions in intensive care patients: A large retrospective observational multicenter study.

PURPOSE: Potential drug-drug interactions (pDDIs) may harm patients admitted to the Intensive Care Unit (ICU). Due to the patient's critical condition and continuous monitoring on the ICU, not all pDDIs are clinically relevant. Clinical decision support systems (CDSSs) warning for irrelevant pDDIs could result in alert fatigue and overlooking important signals. Therefore, our aim was to describe the frequency of clinically relevant pDDIs (crpDDIs) to enable tailoring of CDSSs to the ICU setting. MATERIALS & METHODS: In this multicenter retrospective observational study, we used medication administration data to identify pDDIs in ICU admissions from 13 ICUs. Clinical relevance was based on a Delphi study in which intensivists and hospital pharmacists assessed the clinical relevance of pDDIs for the ICU setting. RESULTS: The mean number of pDDIs per 1000 medication administrations was 70.1, dropping to 31.0 when considering only crpDDIs. Of 103,871 ICU patients, 38% was exposed to a crpDDI. The most frequently occurring crpDDIs involve QT-prolonging agents, digoxin, or NSAIDs. CONCLUSIONS: Considering clinical relevance of pDDIs in the ICU setting is important, as only half of the detected pDDIs were crpDDIs. Therefore, tailoring CDSSs to the ICU may reduce alert fatigue and improve medication safety in ICU patients.

[A young lady with shortness of breath during the coronavirus crisis]. / Een benauwde jongedame tijdens de coronacrisis.

A 16-year-old girl repeatedly visited a general practitioner during the coronavirus pandemic for progressive shortness of breath. Progressive orthopnoea was found as well. Her neck was swollen for two weeks and there was generalised itching for months. Given the nature of her symptoms, she was assessed at the coronavirus station. A diagnosis of coronavirus disease 2019 (COVID-19) was assumed. Due to limited testing capacity, the diagnosis was not confirmed. She was treated with supportive treatment that had no effect on her dyspnoea. Tunnel vision ensured that the symptoms that did not fit COVID-19, were not recognised. Moreover, a scheduled ultrasound of her neck was cancelled because of the coronavirus restrictions, which did not help matters. She was eventually admitted to the paediatric intensive care unit with respiratory failure associated with cervical and mediastinal Hodgkin lymphoma.

Serum tryptase and SCORMA (SCORing MAstocytosis) Index as disease severity parameters in childhood and adult cutaneous mastocytosis.

BACKGROUND: Skin lesions are the predominant clinical feature of the commonest form of mastocytosis. Mastocytosis is classified according to World Health Organization criteria. Determination of the levels of mast-cell mediators or their metabolites reflects the mast-cell burden. The extent of cutaneous mastocytosis can be assessed clinically using a scoring system (SCORing MAstocytosis; SCORMA Index) that we have developed. OBJECTIVE: Serum tryptase levels were compared with the SCORMA Index in a large group of paediatric and adult patients to investigate whether there was any correlation between the two. METHODS: The SCORMA Index in 64 patients (31 children and 33 adults) was compared with serum tryptase levels. The results of the first visit at which SCORMA and tryptase were evaluated were analysed. RESULTS: There was a positive correlation between the SCORMA Index and serum tryptase levels, indicating the value of the SCORMA Index in the assessment of mastocytosis with skin involvement. CONCLUSION: The results of this study showed that the SCORMA Index is a useful tool for evaluating the severity of cutaneous mastocytosis. The correlation between the SCORMA Index and serum tryptase levels underlines the benefit of the SCORMA Index as a clinical tool. Repeated SCORMA Index measurements can provide a rapid impression of changes in the clinical state of mastocytosis. This is particularly relevant in children, because taking blood samples from this group is much more difficult. The well-established methods for evaluation of disease severity may be expanded by the rapid SCORMA Index method.

Acute refractory hyperkalaemia and fatal cardiac arrest related to administration of liposomal amphotericin B.

A 36-year-old male with acute myeloid leukaemia was treated with liposomal amphotericin B for a breakthrough fungal infection with Absidia corymbifera during voriconazole and caspofungin therapy for invasive pulmonary aspergillosis. Four episodes of hyperkalaemia developed with a highly probable relation to infusion of liposomal amphotericin B, of which the last episode was characterised by severe, refractory hyperkalaemia and fatal cardiac arrest. The available literature on severe hyperkalaemia and cardiac arrest during administration of both conventional and liposomal amphotericin B is reviewed here and revealed only four similar cases. The most likely mechanism of toxicity is the release of potassium from a variety of mammal cells including erythrocytes and endothelial cells. Whether prevention of toxicity can be established by decreasing the infusion rate is unclear but conceivable.

Management of invasive pulmonary aspergillosis in non-neutropenic critically ill patients.

During recent years, a rising incidence of invasive pulmonary aspergillosis (IPA) in non-neutropenic critically ill patients has been reported. Critically ill patients are prone to develop disturbances in immunoregulation during their stay in the ICU, which render them more vulnerable for fungal infections. Risk factors such as chronic obstructive pulmonary disease (COPD), prolonged use of steroids, advanced liver disease, chronic renal replacement therapy, near-drowning and diabetes mellitus have been described. Diagnosis of IPA may be difficult and obtaining histo- or cytopathological demonstration of the fungus in order to meet the gold standard for IPA is not always feasible in these patients. Laboratory markers used as a non-invasive diagnostic tool, such as the galactomannan antigen test (GM), 1,3-beta-glucan, and Aspergillus PCR, show varying results. Antifungal therapy might be considered in patients with persistent pulmonary infection who exhibit risk factors together with positive cultures or sequentially positive GM and Aspergillus PCR in serum, in whom voriconazole is the drug of choice. The benefit of combination antifungal therapy lacks sufficient evidence so far, but this treatment might be considered in patients with breakthrough infections or refractory disease.

Spontaneous remission of acute myeloid leukaemia after recovery from sepsis.

Spontaneous remission of acute myeloid leukaemia (AML) is extremely rare and usually of short duration. We report two patients with documented AML who developed spontaneous remission of their leukaemia shortly after an episode of severe sepsis and respiratory failure requiring mechanical ventilation. The underlying mechanisms of spontaneous remission remain unclear but an association with preceding blood transfusions and severe systemic infections has been reported. An overwhelming immune response due to sepsis and leading to raised levels of TNF-alpha, INF-gamma, IL -2 and an increased activity of NK cells, cytotoxic T-cells and macrophages are thought to play an important role. Better insights into the mechanisms of spontaneous remission of AML after recovery from sepsis could help in developing new therapies for AML.