Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies).

Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric patients with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) in five participating European countries. Children were treated for 8 weeks with ODMTs according to an age-appropriate dosing schedule. The primary objective was to describe PK parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (t-max)) of enalapril and its active metabolite enalaprilat. Of 102 patients, 89 patients (n = 26, DCM; n = 63 CHD) were included in the primary PK endpoint analysis. Rate and extent of enalapril and its active metabolite enalaprilat were described and etiology and age could be identified as potential PK modifying factors. The dosing schedule appeared to be tolerated well and did not result in any significant drug-related serious adverse events. The PK analysis and the lack of severe safety events supports the applied age-appropriate dosing schedule for the enalapril ODMTs.

Challenges With Continuous Pulse Oximetry Monitoring and Wireless Clinician Notification Systems After Surgery: Reactive Analysis of a Randomized Controlled Trial.

BACKGROUND: Research has shown that introducing electronic Health (eHealth) patient monitoring interventions can improve healthcare efficiency and clinical outcomes. The VIGILANCE (VItal siGns monItoring with continuous puLse oximetry And wireless cliNiCian notification aftEr surgery) study was a randomized controlled trial (n=2049) designed to assess the impact of continuous vital sign monitoring with alerts sent to nursing staff when respiratory resuscitations with naloxone, code blues, and intensive care unit transfers occurred in a cohort of postsurgical patients in a ward setting. This report identifies and evaluates key issues and challenges associated with introducing wireless monitoring systems into complex hospital infrastructure during the VIGILANCE eHealth intervention implementation. Potential solutions and suggestions for future implementation research are presented. OBJECTIVE: The goals of this study were to: (1) identify issues related to the deployment of the eHealth intervention system of the VIGILANCE study; and (2) evaluate the influence of these issues on intervention adoption. METHODS: During the VIGILANCE study, issues affecting the implementation of the eHealth intervention were documented on case report forms, alarm event forms, and a nursing user feedback questionnaire. These data were collated by the research and nursing personnel and submitted to the research coordinator. In this evaluation report, the clinical adoption framework was used as a guide to organize the identified issues and evaluate their impact. RESULTS: Using the clinical adoption framework, we identified issues within the framework dimensions of people, organization, and implementation at the meso level, as well as standards and funding issues at the macro level. Key issues included: nursing workflow changes with blank alarm forms (24/1030, 2.33%) and missing alarm forms (236/1030, 22.91%), patient withdrawal (110/1030, 10.68%), wireless network connectivity, false alarms (318/1030, 30.87%), monitor malfunction (36/1030, 3.49%), probe issues (16/1030, 1.55%), and wireless network standards. At the micro level, these issues affected the quality of the service in terms of support provided, the quality of the information yielded by the monitors, and the functionality, reliability, and performance of the monitoring system. As a result, these issues impacted access through the decreased ability of nurses to make complete use of the monitors, impacted care quality of the trial intervention through decreased effectiveness, and impacted productivity through interference in the coordination of care, thus decreasing clinical adoption of the monitoring system. CONCLUSIONS: Patient monitoring with eHealth technology in surgical wards has the potential to improve patient outcomes. However, proper planning that includes engagement of front-line nurses, installation of appropriate wireless network infrastructure, and use of comfortable cableless devices is required to maximize the potential of eHealth monitoring. TRIAL REGISTRATION: ClinicalTrials.gov NCT02907255; https://clinicaltrials.gov/ct2/show/NCT02907255.

Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study.

INTRODUCTION: Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. METHODS AND ANALYSIS: Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. ETHICS AND DISSEMINATION: Clinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21.

Vital sign monitoring with continuous pulse oximetry and wireless clinical notification after surgery (the VIGILANCE pilot study)-a randomized controlled pilot trial.

BACKGROUND: Respiratory depression is a serious perioperative complication associated with morbidity and mortality. Recently, technology has become available to wirelessly monitor patients on regular surgical wards with continuous pulse oximetry and wireless clinician notification with alarms. When a patient's SpO2 falls below a set threshold, the clinician is notified via a pager and may intervene earlier to prevent further clinical deterioration. To date, the technology has not been evaluated with a randomized controlled trial (RCT). METHODS: We designed a parallel-group unblinded pilot RCT of a wireless monitoring system on two surgical wards in an academic teaching hospital. Postsurgical patients with an anticipated length of stay of at least 1 day were included and randomized to standard care or standard care plus wireless respiratory monitoring for up to a 72-h period. The primary outcomes were feasibility outcomes: average patients recruited per week and tolerability of the system by patients. Secondary outcomes included (1) respiratory events (naloxone administration for respiratory depression, ICU transfers, and cardiac arrest team activation) and (2) system alarm types and details. The analysis of the outcomes was based on descriptive statistics and estimates reported using point (95% confidence intervals). Criteria for success of feasibility were recruitment of an average of 15 patients/week and 90% of the patients tolerating the system. RESULTS: The pilot trial enrolled 250 of the 335 patients screened for eligibility, with 126 and 124 patients entering the standard monitoring and wireless groups, respectively. Baseline demographics were similar between groups, except for slightly more women in the wireless group. Average patient recruitment per week was 14 95% CI [12, 16] patients. The wireless monitoring was quite tolerable with 86.6% (95% CI 78.2-92.7%) of patients completing the full course, and there were no other adverse events directly attributable to the monitoring. With regard to secondary outcomes, the respiratory event rate was low with only 1 event in the wireless group and none in the control group. The average number of alarms per week was 4.0 (95% CI, 1.6-6.4). CONCLUSIONS: This pilot study demonstrated adequate patient recruitment and high tolerability of the wireless monitoring system. A full RCT that is powered to detect patient important outcomes such as respiratory depression is now underway. TRIAL REGISTRATION: ClinicalTrials.gov, Registration number NCT02907255, registered 7 September 2016-retrospectively registered.

Effect of supplementation with n-3 polyunsaturated fatty acids and/or ß-glucans on performance, feeding behaviour and immune status of Holstein Friesian bull calves during the pre- and post-weaning periods.

BACKGROUND: Previous research in both calves and other species has suggested n-3 polyunsaturated fatty acids (PUFA) and ß-glucans may have positive effects on immune function. This experiment measured performance, behaviour, metabolite and immunological responses to pre-weaning supplementation of dairy bull calves with n-3 PUFA in the form of fish oil and ß-glucans derived from seaweed extract. 44 Holstein Friesian bull calves, aged 13.7 ± 2.5 d and weighing 48.0 ± 5.8 kg were artificially reared using an electronic feeding system. Each calf was offered 5 L (120 g/L) per day of milk replacer (MR) and assigned to one of four treatments included in the MR, (1) Control (CON); (2) 40 g n-3 PUFA per day (FO); (3) 1 g ß-glucans per day (GL) and (4) 40 g n-3 PUFA per day & 1 g/d ß-glucans (FOGL) in a 2 × 2 factorial design. Milk replacer and concentrate was offered from d 0-62 (pre-weaning), while concentrate provision continued for a further 31 d post-weaning period. Individual daily feed intake and feeding behaviour was recorded throughout, while bodyweight and blood analyte data were collected at regular intervals. RESULTS: Overall mean concentrate DMI from d 0-93 was 1.39, 1.27, 1.00 and 0.72 kg/d for CON, FO, GL and FOGL calves, respectively (SEM = 0.037; P < 0.0001). Calves supplemented with GL were significantly lighter (P < 0.0001) at both weaning (d 62) and turnout to pasture (d 93) than un-supplemented calves, with a similar effect (P < 0.0001) evident for calves receiving FO compared to un-supplemented contemporaries. Supplementation with GL reduced the number of unrewarded visits where milk was not consumed (P < 0.0001) while supplementation with FO increased mean drinking speed (P < 0.0001). Supplementation with GL resulted in greater concentrations of haptoglobin (P = 0.034), greater serum osmolality (P = 0.021) and lower lymphocyte levels (P = 0.027). In addition, cells from GL supplemented calves exhibited a lower response than un-supplemented contemporaries to both Phytohaemagglutinin A stimulated IFN-γ (P = 0.019) and Concanavalin A stimulated IFN-γ (P = 0.012) following in vitro challenges. CONCLUSIONS: Pre-weaning supplementation of bull calves with either n-3 PUFA or ß-glucan resulted in reduced voluntary feed intake of concentrate and consequently poorer pre-weaning calf performance. There was no evidence for any beneficial effect of either supplementation strategy on calves' immune responses.

American College of Rheumatology criteria at inception, and accrual over 5 years in the SLICC inception cohort.

OBJECTIVE: To determine the frequency of each American College of Rheumatology (ACR) criterion met at time of enrollment, and the increase in each of the criteria over 5 years. METHODS: In 2000 the Systemic Lupus International Collaborating Clinics (SLICC) recruited an international inception cohort of patients with systemic lupus erythematosus (SLE; ≥ 4 ACR criteria) who were followed at yearly intervals according to a standard protocol. Descriptive statistics were used to assess the total and cumulative number of ACR criteria met at each visit. Regression models were done to compare the increase of individual and cumulative criteria as a function of race/ethnicity group, and sex. RESULTS: In all, 768 patients have been followed for a minimum of 5 years. Overall, 59.1% of the patients had an increase in the number of ACR criteria they met over the 5-year period. The mean number of ACR criteria met at enrollment was 5.04 ± 1.13 and at year 5 was 6.03 ± 1.42. At enrollment, nonwhite patients had a higher number of ACR criteria (5.19 ± 1.23) than white patients. The total number of criteria increased in both white and nonwhite ethnicities, but increased more among whites. Males had a slightly lower number of criteria at enrollment compared to females and males accrued fewer criteria at 5 years. CONCLUSION: In this international inception cohort of SLE patients with at least 4 ACR criteria at entry, there was an accumulation of ACR criteria over the following 5 years. The distribution of criteria both at inception and over 5 years is affected by sex and ethnicity.

Tele-EEG in the UK: a report of over 1,000 patients.

Clinical neurophysiology is the medical specialty in the UK responsible for training doctors in the interpretation of electroencephalograms (EEGs). At present it is difficult to recruit doctors to train in clinical neurophysiology which causes difficulty in delivering services. We established a tele-EEG service to record and report on EEGs at a UK hospital which was unable to attract a resident clinical neurophysiologist. The EEGs were recorded in digital format and placed on a web server to be read by a clinical neurophysiologist in another part of the UK. Where possible this was done using NHS web servers and email, but a back-up system was established using other systems with suitable encryption. A total of 1007 EEGs were reported in 13 months from patients of all ages, epilepsy being the commonest reason for referral. All cases were reported within 24 h of recording. The back-up system was used in 60 cases. Tele-EEG is a feasible, secure, timely and effective method of providing an EEG service to hospitals which cannot recruit a resident clinical neurophysiologist.