An innovative method to strengthen evidence for potential drug safety signals using Electronic Health Records.

Reports from spontaneous reporting systems (SRS) are hypothesis generating. Additional evidence such as more reports is required to determine whether the generated drug-event associations are in fact safety signals. However, underreporting of adverse drug reactions (ADRs) delays signal detection. Through the use of natural language processing, different sources of real-world data can be used to proactively collect additional evidence for potential safety signals. This study aims to explore the feasibility of using Electronic Health Records (EHRs) to identify additional cases based on initial indications from spontaneous ADR reports, with the goal of strengthening the evidence base for potential safety signals. For two confirmed and two potential signals generated by the SRS of the Netherlands Pharmacovigilance Centre Lareb, targeted searches in the EHR of the Leiden University Medical Centre were performed using a text-mining based tool, CTcue. The search for additional cases was done by constructing and running queries in the structured and free-text fields of the EHRs. We identified at least five additional cases for the confirmed signals and one additional case for each potential safety signal. The majority of the identified cases for the confirmed signals were documented in the EHRs before signal detection by the Dutch Medicines Evaluation Board. The identified cases for the potential signals were reported to Lareb as further evidence for signal detection. Our findings highlight the feasibility of performing targeted searches in the EHR based on an underlying hypothesis to provide further evidence for signal generation.

Real-World Metastatic Renal Cell Carcinoma Treatment Patterns and Clinical Outcomes in The Netherlands.

The number of treatment options for patients with metastatic renal cell carcinoma (mRCC) has significantly grown in the last 15 years. Although randomized controlled trials are fundamental in investigating mRCC treatment efficacy, their external validity can be limited. Therefore, the efficacy of the different treatment options should also be evaluated in clinical practice. We performed a chart review of electronic health records using text mining software to study the current treatment patterns and outcomes. mRCC patients from two large hospitals in the Netherlands, starting treatment between January 2015 and May 2020, were included. Data were collected from electronic health records using a validated text mining tool. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Statistical analyses were performed using the Kaplan-Meier method. Most frequent first-line treatments were pazopanib (n = 70), sunitinib (n = 34), and nivolumab with ipilimumab (n = 28). The overall median PFS values for first-line treatment were 15.7 months (95% confidence interval [95%CI], 8.8-20.7), 16.3 months (95%CI, 9.3-not estimable [NE]) for pazopanib, and 6.9 months (95% CI, 4.4-NE) for sunitinib. The overall median OS values were 33.4 months (95%CI, 28.1-50.9 months), 39.3 months (95%CI, 29.5-NE) for pazopanib, and 28.1 months (95%CI, 7.0-NE) for sunitinib. For nivolumab with ipilimumab, median PFS and median OS were not reached. Of the patients who finished first- and second-line treatments, 64 and 62% received follow-up treatments, respectively. With most patients starting on pazopanib and sunitinib, these real-world treatment outcomes were most likely better than in pivotal trials, which may be due to extensive follow-up treatments.

Effectiveness and toxicity of lenvatinib in refractory thyroid cancer: Dutch real-life data.

OBJECTIVE: The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodine-refractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial. METHODS: From three Dutch centres Electronic Health Records (EHRs) of patients treated in the lenvatinib compassionate use program or as standard of care were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in other studies. RESULTS: A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade ≥3 toxicities were hypertension (n = 11, 28%), diarrhoea (n = 7, 18%), vomiting (n = 4, 10%), and gallbladder disease (n = 3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI): 4.0-15.5) and 18.3 (95% CI: 4.9-31.7) months, respectively, response rate was 38% (95% CI: 23-54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (P = 0.04). CONCLUSIONS: PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real-life population and the SELECT study population regarding patient characteristics should be taken into account.

Population pharmacokinetics of treosulfan in paediatric patients undergoing hematopoietic stem cell transplantation.

AIMS: Treosulfan is an alkylating agent increasingly used prior to haematopoietic stem cell transplantation. The aim of this study was to develop a population pharmacokinetic (PK) model of treosulfan in paediatric haematopoietic stem cell transplantation recipients and to explore the effect of potential covariates on treosulfan PK. Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. METHODS: In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m2 treosulfan, administered over 3 consecutive days, were enrolled. A population PK model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. RESULTS: A 2-compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model-based dosing table is presented to target an exposure of 1650 mg*h/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy. CONCLUSIONS: This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3-point LSM allows for accurate and precise estimation of treosulfan exposure.

Personalized busulfan and treosulfan conditioning for pediatric stem cell transplantation: the role of pharmacogenetics and pharmacokinetics.

Busulfan- and treosulfan-based conditionings are the cornerstone of pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Although both drugs are alkylating agents, their mechanisms of action, pharmacokinetics (PK) and toxicity profiles are different. Experience with busulfan in pediatric HSCT is broad and the knowledge on the pharmacodynamics (PD), PK and, to a lesser extent, pharmacogenetics (PG) has resulted in a more effective therapy. Treosulfan has only recently been introduced in pediatric HSCT and is considered a promising new therapy because of its beneficial toxicity profile. However, knowledge of the PK and PG of treosulfan is limited. In this review, we describe the pharmacology of both agents and discuss factors causing variability in PK in relation to therapeutic outcome in HSCT.

Effect of genetic polymorphisms in genes encoding GST isoenzymes on BU pharmacokinetics in adult patients undergoing hematopoietic SCT.

BU is used in conditioning regimens before hemopoietic SCT. High BU exposure is associated with toxicity, whereas low BU exposure leads to higher rates of therapy failure. The pharmacokinetics of BU show large interpatient variability, hypothesized to be caused by variability in BU metabolism. In this report, the effect of genetic polymorphisms in three gluthatione S-transferase genes involved in BU metabolism (hGSTA1), GSTM1 (deletion-mutation) and GSTP1 (313A/G) on the pharmacokinetics of BU in Caucasian adult patients was investigated. In all, 66 adult patients received BU as part of their conditioning regimen. After the first infusion, two serum samples were collected and measured using a HPLC assay. A one-compartment population model was used to estimate individual pharmacokinetic parameters. The genetic variants of the three glutathione S-transferase (GST) genes were determined by pyrosequencing and PCR. A reduction of 14% in BU clearance was seen for the GSTA1*B allele and an increase in BU exposure was found. No relationship was found between polymorphisms in GSTM1 and GSTP1 and BU pharmacokinetics. This study shows that an increasing number of copies of GSTA1*B allele results in a significant decrease of BU clearance.

Intensive care medicine trainees' perception of professionalism: a qualitative study.

The Competency-Based Training program in Intensive Care Medicine in Europe identified 12 competency domains. Professionalism was given a prominence equal to technical ability. However, little information pertaining to fellows' views on professionalism is available. A nationwide qualitative study was performed. The moderator asked participants to clarify the terms professionalism and professional behaviour, and to explore the questions "How do you learn the mentioned aspects?" and "What ways of learning do you find useful or superfluous?". Qualitative data analysis software (MAXQDA2007) facilitated analysis using an inductive coding approach. Thirty-five fellows across eight groups participated. The themes most frequently addressed were communication, keeping distance and boundaries, medical knowledge and expertise, respect, teamwork, leadership and organisation and management. Medical knowledge, expertise and technical skills seem to become more tacit when training progresses. Topics can be categorised into themes of workplace-based learning, by gathering practical experience, by following examples and receiving feedback on action, including learning from own and others' mistakes. Formal teaching courses (e.g. communication) and scheduled sessions addressing professionalism aspects were also valued. The emerging themes considered most relevant for intensivists were adequate communication skills and keeping boundaries with patients and relatives. Professionalism is mainly learned 'on the job' from role models in the intensive care unit. Formal teaching courses and sessions addressing professionalism aspects were nevertheless valued, and learning from own and others' mistakes was considered especially useful. Self-reflection as a starting point for learning professionalism was stressed.

Diagnostic and therapeutic management for suspected neonatal herpes simplex virus infection.

BACKGROUND: Neonatal herpes simplex virus (HSV) is a rare disease associated with high mortality and morbidity rates. HSV infection can be subdivided into 3 clinical manifestations: isolated skin, eye and mouth (SEM) disease, central nervous system (CNS) disease and disseminated disease. Consensus guidelines for diagnostic and therapeutic management are not available. OBJECTIVES: To evaluate the diagnostic work-up and therapeutic management in neonates with suspected or proven HSV infection. STUDY DESIGN: Retrospective study of diagnostic and therapeutic management in all neonates with suspected HSV infection admitted to our neonatal nursery between January 2005 and July 2010. RESULTS: A total 53 neonates with suspected HSV infection were included in the study and classified as SEM disease (n=2), CNS disease (n=41) or disseminated disease (n=10). None of the included infants tested positive for HSV infection. Correct and complete diagnostic work-up was performed in only 11% (6/53) of the cases. All neonates were treated with intravenous acyclovir. CONCLUSIONS: None of the neonates with suspected HSV tested positive. Diagnostic management in neonates with suspected HSV infection was often improper and incomplete. Consensus guidelines to identify low-risk infants in whom HSV testing and acyclovir treatment is not warranted, are urgently needed.

Results of streamlined regional ambulance transport and subsequent treatment of acute abdominal aortic aneurysms.

OBJECTIVE: To describe the triage of patients operated for non-ruptured and ruptured abdominal aortic aneurysms (AAAs) before the endovascular era. DESIGN: Retrospective single-centre cohort study. METHODS: All patients treated for an acute AAA between 1998 and 2001 and admitted to our hospital were evaluated in the emergency department for urgent AAA surgery. All time intervals, from the telephone call from the patient to the ambulance department, to the arrival of the patient in the operating theatre, were analysed. Intraoperative, hospital and 1-year survival were determined. RESULTS: 160 patients with an acute AAA were transported to our hospital. Mean (SD) age was 71 (8) years, and 138 (86%) were men. 34 (21%) of these patients had symptomatic, non-ruptured AAA (sAAA) and 126 patients had ruptured AAA (rAAA). All patients with sAAA and 98% of patients with rAAA were operated upon. For the patients with rAAA, median time from telephone call to arrival at the hospital was 43 min (interquartile range 33-53 min) and median time from arrival at the hospital to arrival at the operating room was 25 min (interquartile range 11-50 min). Intraoperative mortality was 0% for sAAA and 11% for rAAA (p = 0.042), and hospital mortality was 12% and 33%, respectively (p = 0.014). CONCLUSIONS: A multidisciplinary unified strategy resulted in a rapid throughput of patients with acute AAA. Rapid transport, diagnosis and surgery resulted in favourable hospital mortality. Despite the fact that nearly all the patients were operated upon, survival was favourable compared with published data.

Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity.

We studied the pharmacokinetics of intravenous busulfan (Bu) in children in order to further optimize intravenous Bu dosing in relation to toxicity and survival. A total of 31 children undergoing Bu-based conditioning for allogeneic SCT were enrolled in a study. The starting dose was 1.0 mg/kg (age < 4 years) and 0.8 mg/kg (age > or =4 years), four doses per day during 4 days. Dose adjustment was allowed up to a maximum dose of 1.0 mg/kg per dose if the target area under the serum concentration-time curve (AUC) was not reached. Pharmacokinetic studies were performed after the first dose. Donor engraftment was established in 28 out of 31 patients. The average AUC after the first dose was the same in children < 4 years as in children > or =4 years. Mean clearance was higher in children < 4 years than in children > or =4 years. In 35% of all patients, total AUC was within the target AUC. The other children's AUCs were below the target range. No relationships were found between systemic exposure to Bu and toxicity or clinical outcome. We concluded that, in accordance with previous data, within the observed AUCs no clear relationship was observed between Bu AUC and outcome with respect to toxicity, engraftment and relapse.

Pharmacokinetics of rectal tramadol in postoperative paediatric patients.

BACKGROUND: Postoperative analgesia in children may be improved by using tramadol. The pharmacokinetics of rectal tramadol in young children were therefore investigated. METHODS: The pharmacokinetics of rectal tramadol and its active metabolite were studied in 12 young children (age: 1-6 yr) postoperatively. On the basis of these data, a population model was constructed. Using this model, the pharmacokinetics of different doses of tramadol were calculated. RESULTS: The pharmacokinetics of rectal tramadol could be adequately described by a one-compartment model. The pharmacokinetic parameters derived from the model indicate that a low variability was present. Elimination half-life was 4.3 (0.2) h (sem) and the apparent clearance was 16.4 (1.5) litre h(-1) (sem). CONCLUSIONS: The study showed that after rectal administration, tramadol is absorbed at a reasonable rate and with a low inter-individual variability in small children. The data also suggested that a rectal dose of tramadol 1.5-2.0 mg kg(-1) is therapeutic.

Cost effectiveness of selective decontamination of the digestive tract in liver transplant patients.

OBJECTIVE: To assess the cost effectiveness of selective decontamination of the digestive tract (SDD) in liver transplant patients. DESIGN: Randomised, placebo-controlled, double-blind trial with an integrated economic evaluation. SETTING: Two university hospitals in The Netherlands. Cost effectiveness was assessed from a societal perspective. PATIENTS AND PARTICIPANTS: 58 patients who underwent liver transplantation and received SDD (n = 29) or placebo (n = 29) pre- and postoperatively. INTERVENTIONS: SDD medication and placebo. MAIN OUTCOME MEASURES: Infection episodes, days of infection, costs of SDD and routine cultures, mean other direct medical costs per patient and additional costs of severe infection. RESULTS: Costs of SDD medicine and routine cultures were on average 3,100 US dollars ($US; 1997 values) per patient who underwent SDD. Both preoperatively and postoperatively, costs other than SDD and cultures did not significantly differ between the SDD and the placebo groups (preoperative, $US2,370 vs $US2,590; postoperative, $US25,455 vs $US24,915). Additional postoperative costs of severe infections were $US250 per day per patient. There were no significant differences in the mean number of infection episodes between groups. CONCLUSIONS: SDD leads to the additional costs of SDD medication and routine cultures, whereas no savings in other costs and no improvement in infection episodes are realised. Consequently, SDD may be considered as a nonefficient approach in patients undergoing liver transplantation. The additional costs of severe infection are considerable.

The abdominal compartment syndrome: a complication with many faces.

BACKGROUND: Lately renewed attention has been given to the abdominal compartment syndrome. Despite of this there still remain a lot of controversies with regard to the pathophysiological mechanisms underlying this syndrome and the therapeutic options. METHODS: Two cases of patients with this syndrome are described and the data from animal and human trials concerning the abdominal compartment syndrome are presented and discussed. RESULTS: A variety of clinical disorders may lead to the abdominal compartment syndrome. It mainly affects the cardiovascular, pulmonary and renal organ systems. Although some clinical effects are clearly described, the exact mechanisms underlying these changes in humans are incompletely understood. It is still unclear why some patients develop abdominal compartment syndrome and others do not. The intra-abdominal pressure can easily be assessed by measuring the urine bladder pressure, which correlates well with the actual intra-abdominal pressure. All authors agree that a decompression of the abdomen by means of a laparotomy is the treatment of choice for the abdominal compartment syndrome. Which parameters should determine the indication however, remains controversial, since the correlation between clinical signs and pressure is not straightforward. CONCLUSIONS: The abdominal compartment syndrome is a well-recognised disease entity related to acutely increased abdominal pressure. Urgent laparotomy can be lifesaving in some cases. However no single threshold of abdominal pressure can be applied universally. Pending further clinical trials the best therapeutic option seems to be to decompress the abdomen surgically if the intravesical pressure is 25 mmHg or higher in patients with refractory hypotension, acute renal failure or respiratory failure due to abdominal distension.

Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study.

OBJECTIVE: This study investigated whether treatment with the anti-tumor necrosis factor-alpha monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/mL. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: Eighty-four intensive care units in academic medical centers in Europe and Israel. PATIENTS: A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222). Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days. INTERVENTIONS: Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered. MEASUREMENTS AND MAIN RESULTS: The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p <.001) than that found in the randomized patients (55.8%, 249 of 446). The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs. 57.7% (128 of 222), respectively. Treatment with afelimomab was not associated with any particular adverse events. CONCLUSIONS: The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.

Retransplantation of the liver in children.

BACKGROUND: Because of the poor outcome of hepatic retransplantation, it is still debated whether this procedure should be performed in an era of donor organ scarcity. The aim of this study was to analyze outcome of hepatic retransplantation in children, to identify risk factors influencing this outcome, and to assess morbidity and causes of death. METHODS: A series of 97 children after a single transplantation and 34 children with one retransplantation was analyzed. RESULTS: The 1-, 3-, and 5-year survival of children with a retransplantation was 70, 63, and 52%, respectively, compared with 85, 82, and 78%, respectively, for children after a single transplantation (P=0.009). Survival of children with a retransplantation within 1 month after primary transplantation was worse (P=0.007) and survival of children with a late retransplantation was comparable (P=0.66) with single transplantation. In early retransplantations, the Child-Pugh score was higher, donors were older and weighed more, and more technical variant liver grafts were used compared with single transplantations. Biliary atresia and a high Child-Pugh score were associated with decreased patient survival after retransplantation. Sepsis was the most important complication and cause of death after retransplantation. CONCLUSIONS: Retransplantation is a significant event after pediatric liver transplantation. Outcome after hepatic retransplantation in children is inferior compared with single transplantation. This difference is explained by low survival after early retransplantation and can be explained by the poor clinical condition of the children at time of retransplantation, especially in children with biliary atresia, and by the predominant use of technical variant liver grafts in retransplantations.

Prognostic factors for long-term actual patient survival after orthotopic liver transplantation in children.

BACKGROUND: Orthotopic liver transplantation has become the treatment of choice for children with end-stage liver disease. Although results have improved the last decades, still a considerable number of children die after transplantation. The aim of this study was to analyze long-term actual survival and to identify prognostic factors for such survival rates. METHODS: A consecutive series of 66 children receiving transplants who had or could have had a follow-up of at least 5 years was retrospectively analyzed. Actual survival and prognostic factors in relation to patient, donor, and operation related variables were assessed after multivariate analysis. RESULTS: Actual 1-, 3-, and 5-year patient survival was 86%, 79%, and 73%, respectively. A high Child-Pugh (C-P) score or C-P class C, high donor age, high blood loss index, and retransplantation were predictive factors for actual patient survival. A high blood loss index was correlated with biliary atresia, low recipient age and weight, and with previous upper abdominal operations. The duration of stay of the donor at the intensive care unit (ICU) was a predictive factor for retransplantation. CONCLUSIONS: Children with diseases eligible for liver transplantation should be seen early in the course of their disease in a transplantation center. All possible measures should be taken during the transplantation procedure to keep the blood loss at a minimum. Children with biliary atresia deserve special attention in this respect. The choice of donors has implications for survival.

Selective digestive decontamination in patients in intensive care. The Dutch Working Group on Antibiotic Policy.

Selective digestive decontamination (SDD) is the most extensively studied method for the prevention of infection in patients in intensive care units (ICUs). Despite 27 prospective randomized studies and six meta-analyses, routine use of SDD is still controversial. In this review, we summarize the available scientific information on effectiveness of SDD in ICU patients. The effects of SDD have been studied in different combinations of the concept, using different antibiotics. Comparison of the individual studies, therefore, is difficult. In most studies, SDD resulted in significant reductions in the number of diagnoses of ventilator-associated pneumonia. However, incidences of ventilator-associated pneumonia in control groups ranged from 5% to 85%. Moreover, these reductions in incidences of ventilator-associated pneumonia in individual studies were not associated with improved patient survival, reductions of duration of ventilation or ICU stay, or reductions in antibiotic use. The numbers of patients studied are too small to determine effects on patient survival. Although two meta-analyses suggested a 20% mortality reduction when using the full concept of SDD (topical and systemic prophylaxis) these results should be interpreted with caution. Formal cost-benefit analyses of SDD have not been performed. SDD is associated with the selection of microorganisms that are intrinsically resistant to the antibiotics used. However, the studies are too small and too short to investigate whether SDD will lead to development of antibiotic resistance. As long as the benefits of SDD (better patient survival, reduction in antibiotic use or improved cost-effectiveness) have not been firmly established, the routine use of SDD for mechanically ventilated patients is not advised.

Endotoxins and cytokines during liver transplantation: changes in plasma levels and effects on clinical outcome.

Endotoxins, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6 are believed to have a key role in liver transplantation. The origin and course of these factors is not completely known. In this prospective study of 40 patients, we sought more understanding of the relations between these factors and their effects on clinical outcome by sampling at different sites. Endotoxemia was only present in 20% of the patients. In 75% of these patients, it was present during the anhepatic phase and quickly resolved after reperfusion. Endotoxemia was not related to a clinical adverse event. TNF-alpha was released from the graft after reperfusion, and initial levels after reperfusion were related to predonation levels in the donor. Only levels of TNF-alpha in the recipient before transplantation were found to be predictive of postoperative complications. We conclude that monitoring endotoxins and these cytokines is of very limited value in predicting outcome.