RELATIONSHIPS, RIGHTS, AND RESPONSIBILITIES: (RE)VIEWING THE NHS CONSTITUTION FOR THE POST-PANDEMIC 'NEW NORMAL'.

Action needs to be taken to map out the fairest way to meet the needs of all NHS stakeholders in the post-pandemic 'new normal'. In this article, we review the NHS Constitution, looking at it from a relational perspective and suggesting that it offers a useful starting point for such a project, but that new ways of thinking are required to accommodate the significant changes the pandemic has made to the fabric of the NHS. These new ways of thinking should encompass concepts of solidarity, care, and (reciprocal) responsibility, grounded in an acceptance of the importance of relationships in society. To this end, we explore and emphasise the importance of our interconnections as NHS stakeholders and 're-view' the NHS Constitution from a relational perspective, concentrating on the rights and responsibilities it describes for patients and the public as NHS stakeholders. We argue that the NHS Constitution, of which most stakeholders are probably unaware, can be used as a tool to engage us, and to catalyse conversation about how our responsibilities as NHS stakeholders should change in the post-pandemic 'new normal'.

Which ethical values underpin England's National Health Service reset of paediatric and maternity services following COVID-19: a rapid review.

OBJECTIVE: To identify ethical values guiding decision making in resetting non-COVID-19 paediatric surgery and maternity services in the National Health Service (NHS). DESIGN: A rapid review of academic and grey literature sources from 29 April to 31 December 2020, covering non-urgent, non-COVID-19 healthcare. Sources were thematically synthesised against an adapted version of the UK Government's Pandemic Flu Ethical Framework to identify underpinning ethical principles. The strength of normative engagement and the quality of the sources were also assessed. SETTING: NHS maternity and paediatric surgery services in England. RESULTS: Searches conducted 8 September-12 October 2020, and updated in March 2021, identified 48 sources meeting the inclusion criteria. Themes that arose include: staff safety; collaborative working - including mutual dependencies across the healthcare system; reciprocity; and inclusivity in service recovery, for example, by addressing inequalities in service access. Embedded in the theme of staff and patient safety is embracing new ways of working, such as the rapid roll out of telemedicine. On assessment, many sources did not explicitly consider how ethical principles might be applied or balanced against one another. Weaknesses in the policy sources included a lack of public and user involvement and the absence of monitoring and evaluation criteria. CONCLUSIONS: Our findings suggest that relationality is a prominent ethical principle informing resetting NHS non-COVID-19 paediatric surgery and maternity services. Sources explicitly highlight the ethical importance of seeking to minimise disruption to caring and dependent relationships, while simultaneously attending to public safety. Engagement with ethical principles was ethics-lite, with sources mentioning principles in passing rather than explicitly applying them. This leaves decision makers and healthcare professionals without an operationalisable ethical framework to apply to difficult reset decisions and risks inconsistencies in decision making. We recommend further research to confirm or refine the usefulness of the reset phase ethical framework developed through our analysis.

Procalcitonin, C-reactive protein, neutrophil gelatinase-associated lipocalin, resistin and the APTT waveform for the early diagnosis of serious bacterial infection and prediction of outcome in critically ill children.

OBJECTIVE: Bacterial Infections remains a leading cause of death in the Paediatric Intensive Care Unit (PICU). In this era of rising antimicrobial resistance, new tools are needed to guide antimicrobial use. The aim of this study was to investigate the accuracy of procalcitonin (PCT), neutrophil gelatinase-associated lipocalin (NGAL), resistin, activated partial thromboplastin time (aPTT) waveform and C-reactive protein (CRP) for the diagnosis of serious bacterial infection (SBI) in children on admission to PICU and their use as prognostic indicators. SETTING: A regional PICU in the United Kingdom. PATIENTS: Consecutive PICU admissions between October 2010 and June 2012. MEASUREMENTS: Blood samples were collected daily for biomarker measurement. The primary outcome measure was performance of study biomarkers for diagnosis of SBI on admission to PICU based on clinical, radiological and microbiological criteria. Secondary outcomes included durations of PICU stay and invasive ventilation and 28-day mortality. Patients were followed up to day 28 post-admission. MAIN RESULTS: A total of 657 patients were included in the study. 92 patients (14%) fulfilled criteria for SBI. 28-day mortality was 2.6% (17/657), but 8.7% (8/92) for patients with SBI. The combination of PCT, resistin, plasma NGAL and CRP resulted in the greatest net reclassification improvement compared to CRP alone (0.69, p<0.005) with 10.5% reduction in correct classification of patients with SBI (p 0.52) but a 78% improvement in correct classification of patients without events (p <0.005). A statistical model of prolonged duration of PICU stay found log-transformed maximum values of biomarkers performed better than first recorded biomarkers. The final model included maximum values of CRP, plasma NGAL, lymphocyte and platelet count (AUC 79%, 95% CI 73.7% to 84.2%). Longitudinal profiles of biomarkers showed PCT levels to decrease most rapidly following admission SBI. CONCLUSION: Combinations of biomarkers, including PCT, may improve accurate and timely identification of SBI on admission to PICU.

Title NMR-based metabolic profiling provides diagnostic and prognostic information in critically ill children with suspected infection.

Sepsis, defined as life-threatening organ dysfunction caused by infection is difficult to distinguish clinically from infection or post-operative inflammation. We hypothesized that in a heterogeneous group of critically ill children, there would be different metabolic profiles between post-operative inflammation, bacterial and viral infection and infection with or without organ dysfunction. 1D 1H nuclear magnetic resonance spectra were acquired in plasma samples from critically ill children. We included children with bacterial (n = 25) and viral infection (n = 30) and controls (n = 58) (elective cardiac surgery without infection). Principal component analysis was used for data exploration and partial least squares discriminant analysis models for the differences between groups. Area under receiver operating characteristic curve (AUC) values were used to evaluate the models. Univariate analysis demonstrated differences between controls and bacterial and viral infection. There was excellent discrimination between bacterial and control (AUC = 0.94), and viral and control (AUC = 0.83), with slightly more modest discrimination between bacterial and viral (AUC = 0.78). There was modest discrimination (AUC = 0.73) between sepsis with organ dysfunction and infection with no organ dysfunction. In critically ill children, NMR metabolomics differentiates well between those with a post-operative inflammation but no infection, and those with infection (bacterial and viral), and between sepsis and infection.

Identifying critically ill children at high risk of acute kidney injury and renal replacement therapy.

Acute kidney injury (AKI), a common complication in paediatric intensive care units (PICU), is associated with increased morbidity and mortality. In this single centre, prospective, observational cohort study, neutrophil gelatinase-associated lipocalin in urine (uNGAL) and plasma (pNGAL) and renal angina index (RAI), and combinations of these markers, were assessed for their ability to predict severe (stage 2 or 3) AKI in children and young people admitted to PICU. In PICU children and young people had initial and serial uNGAL and pNGAL measurements, RAI calculation on day 1, and collection of clinical data, including serum creatinine measurements. Primary outcomes were severe AKI and renal replacement therapy (RRT). Secondary outcomes were length of stay, hospital acquired infection and mortality. The area under the Receiver Operating Characteristic (ROC) curves and Youden index was used to determine biomarker performance and identify optimum cut-off values. Of 657 children recruited, 104 met criteria for severe AKI (15∙8%) and 47 (7∙2%) required RRT. Severe AKI was associated with increased length of stay, hospital acquired infection, and mortality. The area under the curve (AUC) for severe AKI prediction for Day 1 uNGAL, Day 1 pNGAL and RAI were 0.75 (95% Confidence Interval [CI] 0∙69, 0∙81), 0∙64 (95% CI 0∙56, 0∙72), and 0.73 (95% CI 0∙65, 0∙80) respectively. The optimal combination of measures was RAI and day 1 uNGAL, giving an AUC of 0∙80 for severe AKI prediction (95% CI 0∙71, 0∙88). In this heterogenous PICU cohort, urine or plasma NGAL in isolation had poorer prediction accuracy for severe AKI than in previously reported homogeneous populations. However, when combined together with RAI, they produced good prediction for severe AKI.

Supporting children and young people when making decisions about joining clinical trials: qualitative study to inform multimedia website development.

OBJECTIVES: To understand stakeholders' views regarding the content and design of paediatric clinical trial multimedia websites. To describe how this knowledge informed the development of the multimedia websites. DESIGN: Qualitative study comprising two rounds of interviews or focus groups, with thematic analysis of interview transcripts. PARTICIPANTS: Sixty-two people (21 children and young people with long-term health conditions, 24 parents and 17 professionals). SETTING: One UK children's hospital and one UK Young Persons' Advisory Group. RESULTS: When asked what was important in deciding whether to join a trial, children, young people and parents prioritised information about what participation would involve, what the trial was testing, potential benefits and risks of participation and knowing they could leave the trial if they later changed their minds. Young people and parents trusted trial teams to follow regulatory and quality requirements and therefore did not think such information was a priority for the websites, although logos of trusted organisations could lend credibility. Professionals largely concurred with these views. Children and young people advised on the importance of designing the multimedia website to ensure its appearance, tone and wording suited the intended audience and on using animated characters to facilitate children's engagement. CONCLUSIONS: Our study provides insights into the information that families value when deciding about healthcare trial participation. It provides guidance on the design of information resources to appeal to children and young people, while also being acceptable to parents and professionals who are often gatekeepers of children's access to information. Our findings will be of use to others developing similar multimedia websites. We report specific information needs and new visual preferences that are not usually addressed in printed trial information. Our work illustrates what qualitative research and participatory design practices can contribute to the development of information resources more generally. TRIAL REGISTRATION NUMBER: ISRCTN73136092; Pre-results.

Procalcitonin and Other Common Biomarkers Do Not Reliably Identify Patients at Risk for Bacterial Infection After Congenital Heart Surgery.

OBJECTIVES: Following surgery, it is difficult to distinguish a postoperative inflammatory reaction from infection. This study examined the predictive value of the biomarkers; procalcitonin, C-reactive protein, lactate, neutrophils, lymphocytes, platelets, and the biphasic activated partial thromboplastin time waveform in diagnosing bacterial infection following cardiac surgery. DESIGN: Prospective, observational study. SETTING: A regional, PICU in the United Kingdom. PATIENTS: Three-hundred sixty-eight children under the age of 16 admitted to the PICU for elective cardiac surgery were enrolled in the study. INTERVENTIONS: All biomarker measurements were determined daily until postoperative day 7. Children were assessed for postoperative infection until day 28 and divided into four groups: bacterial infection, culture-negative sepsis, viral infection, and no infection. We used the Kruskal-Wallis test, chi-square test, analysis of variance, and area under the curve in our analysis. MEASUREMENTS AND MAIN RESULTS: In total, 71 of 368 children (19%) developed bacterial infection postoperatively, the majority being surgical site infections. In those with bacterial infection, procalcitonin was elevated on postoperative days 1-3 and the last measurement prior to event compared with those without bacterial infection. The most significant difference was the last measurement prior to event; 0.72 ng/mL in the bacterial infection group versus 0.13 ng/mL in the no infection group (for all groups; p < 0.001). Longitudinal profiles of all biomarkers were indistinct in the bacterial infection and nonbacterial infection groups except in those with culture-negative infections who had distinct procalcitonin kinetics on postoperative days 1-4. Children with culture-negative sepsis required longer ventilatory support and PICU stay and were more likely to develop complications than the other groups. CONCLUSIONS: None of the biomarkers studied within 3 days of infection distinguished between infection and postoperative inflammatory reaction. However, procalcitonin kinetics peaked on postoperative day 2 and fell more sharply than C-reactive protein kinetics, which peaked at postoperative day 3. The monitoring of procalcitonin kinetics following cardiac surgery may help guide rational antimicrobial use.

Patterns of Instability Associated With Endotracheal Suctioning in Infants With Single-Ventricle Physiology.

BACKGROUND: In infants with single-ventricle physiology, endotracheal suctioning poses risks because of the instability between pulmonary and systemic blood flow. OBJECTIVE: To examine processes and adverse events associated with endotracheal suctioning in the first 48 hours after 3 surgical procedures: the Norwood or Norwood-Sano procedure, pulmonary artery banding, and the modified Blalock-Taussig shunt. METHODS: Prospective observational study in a pediatric intensive care unit. RESULTS: Bedside nurses collected data from 211 episodes of endotracheal suctioning in 24 infants. Most (62%,130/211) suction episodes were unplanned; 38% (81/211) were planned. The most common reason for unplanned suctioning was arterial desaturation (48%, 62/130 episodes). The infants' oxygen saturation levels before suctioning ranged from 27% to 86%. Serious adverse events occurred in 9% (19/211) of suction episodes. In 8 (42%) of the episodes involving a serious adverse event, the patient received no additional intravenous bolus of analgesic or muscle relaxant before suctioning; in 8 episodes (42%), the patient received both an analgesic and a relaxant; in 3 episodes (16%), the patient received either an analgesic or a relaxant but not both. More adverse events occurred with open suctioning (68%, 13/19) than with closed suctioning (32%, 6/19). Most adverse events (68%, 13/19) occurred during the night shift. CONCLUSIONS: Significant hemodynamic instability and adverse events occur during routine suctioning in infants with single-ventricle physiology after surgical palliation.

Family interests and medical decisions for children.

Medical decisions for children are usually justified by the claim that they are in a child's best interests. More recently, following criticisms of the best interests standard, some advocate that the family's interests should influence medical decisions for children, although what is meant by family interests is often not made clear. I argue that at least two senses of family interests may be discerned. There is a 'weak' sense (as the amalgamated interests of family members) of family interests and a 'strong' sense (that the family itself has interests over and above the interests of individuals). I contend that there are problems with both approaches in making medical decisions for children but that the weak sense is more plausible. Despite this, I argue that claims for family interests are not helpful in making medical decisions for children.

Developing and evaluating multimedia information resources to improve engagement of children, adolescents, and their parents with trials (TRECA study): Study protocol for a series of linked randomised controlled trials.

BACKGROUND: Randomised controlled trials are widely established as the best method for testing health interventions whilst minimising bias. However, recruitment and subsequent retention of children and adolescents in healthcare trials is challenging. Participant information sheets are often lengthy and difficult to read and understand. Presenting key information using multimedia may help to overcome these limitations and better support young people and their parents in deciding whether to participate in a clinical trial. METHODS: The TRECA (TRials Engagement in Children and Adolescents) study has two phases. The first phase involves a qualitative study with children and adolescents and their parents to inform the development of multimedia information resources and iterative user testing to refine the resources. The second phase will embed the use of the multimedia information resources into six host trials in the United Kingdom. Patients and parents approached to participate in the host trials will be randomly allocated to either use the multimedia information resource in conjunction with standard participant information sheets, the multimedia information resource alone, or the standard participant information sheets alone. The primary outcome will be the effect of the multimedia information resources on recruitment into trials. Other outcomes measured include the effect of multimedia information resources on retention of participants into the host trials and the impact on family members' decision-making processes, when compared to standard participant information sheets alone. DISCUSSION: This study will inform whether multimedia information resources, when developed using participatory design principles, are able to increase recruitment and retention of children and adolescents into trials. There is also the potential for patients to make better informed decisions through the use of multimedia information resources. The multimedia information resources also have the potential to assist with providing information on other healthcare decisions outside of clinical trials. TRIAL REGISTRATION: ISRCTN registry: ISRCTN73136092 (doi: 10.1186/ISRCTN73136092 ). Registered on 24 August 2016.

Pilot Study Comparing Closed Versus Open Tracheal Suctioning in Postoperative Neonates and Infants With Complex Congenital Heart Disease.

OBJECTIVES: To determine the hemodynamic effect of tracheal suction method in the first 36 hours after high-risk infant heart surgery on the PICU and to compare open and closed suctioning techniques. DESIGN: Pilot randomized crossover study. SETTING: Single PICU in United Kingdom. PARTICIPANTS: Infants undergoing surgical palliation with Norwood Sano, modified Blalock-Taussig shunt, or pulmonary artery banding in the first 36 hours postoperatively. INTERVENTIONS: Infants were randomized to receive open or closed (in-line) tracheal suctioning either for their first or second study tracheal suction in the first 36 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: Twenty-four infants were enrolled over 18 months, 11 after modified Blalock-Taussig shunt, seven after Norwood Sano, and six after pulmonary artery banding. Thirteen patients received the open suction method first followed by the closed suction method second, and 11 patients received the closed suction method first followed by the open suction method second in the first 36 hours after their surgery. There were statistically significant larger changes in heart rate (p = 0.002), systolic blood pressure (p = 0.022), diastolic blood pressure (p = 0.009), mean blood pressure (p = 0.007), and arterial saturation (p = 0.040) using the open suction method, compared with closed suctioning, although none were clinically significant (defined as requiring any intervention). CONCLUSIONS: There were no clinically significant differences between closed and open tracheal suction methods; however, there were statistically significant greater changes in some hemodynamic variables with open tracheal suctioning, suggesting that closed technique may be safer in children with more precarious physiology.

Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children.

BACKGROUND: Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are limited. METHODS: In a trial conducted at 37 children's hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest. RESULTS: The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups. CONCLUSIONS: Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087 .).

A clinical and economic evaluation of Control of Hyperglycaemia in Paediatric intensive care (CHiP): a randomised controlled trial.

BACKGROUND: Early research in adults admitted to intensive care suggested that tight control of blood glucose during acute illness can be associated with reductions in mortality, length of hospital stay and complications such as infection and renal failure. Prior to our study, it was unclear whether or not children could also benefit from tight control of blood glucose during critical illness. OBJECTIVES: This study aimed to determine if controlling blood glucose using insulin in paediatric intensive care units (PICUs) reduces mortality and morbidity and is cost-effective, whether or not admission follows cardiac surgery. DESIGN: Randomised open two-arm parallel group superiority design with central randomisation with minimisation. Analysis was on an intention-to-treat basis. Following random allocation, care givers and outcome assessors were no longer blind to allocation. SETTING: The setting was 13 English PICUs. PARTICIPANTS: Patients who met the following criteria were eligible for inclusion: ≥ 36 weeks corrected gestational age; ≤ 16 years; in the PICU following injury, following major surgery or with critical illness; anticipated treatment > 12 hours; arterial line; mechanical ventilation; and vasoactive drugs. Exclusion criteria were as follows: diabetes mellitus; inborn error of metabolism; treatment withdrawal considered; in the PICU > 5 consecutive days; and already in CHiP (Control of Hyperglycaemia in Paediatric intensive care). INTERVENTION: The intervention was tight glycaemic control (TGC): insulin by intravenous infusion titrated to maintain blood glucose between 4.0 and 7.0 mmol/l. CONVENTIONAL MANAGEMENT (CM): This consisted of insulin by intravenous infusion only if blood glucose exceeded 12.0 mmol/l on two samples at least 30 minutes apart; insulin was stopped when blood glucose fell below 10.0 mmol/l. MAIN OUTCOME MEASURES: The primary outcome was the number of days alive and free from mechanical ventilation within 30 days of trial entry (VFD-30). The secondary outcomes comprised clinical and economic outcomes at 30 days and 12 months and lifetime cost-effectiveness, which included costs per quality-adjusted life-year. RESULTS: CHiP recruited from May 2008 to September 2011. In total, 19,924 children were screened and 1369 eligible patients were randomised (TGC, 694; CM, 675), 60% of whom were in the cardiac surgery stratum. The randomised groups were comparable at trial entry. More children in the TGC than in the CM arm received insulin (66% vs. 16%). The mean VFD-30 was 23 [mean difference 0.36; 95% confidence interval (CI) -0.42 to 1.14]. The effect did not differ among prespecified subgroups. Hypoglycaemia occurred significantly more often in the TGC than in the CM arm (moderate, 12.5% vs. 3.1%; severe, 7.3% vs. 1.5%). Mean 30-day costs were similar between arms, but mean 12-month costs were lower in the TGC than in CM arm (incremental costs -£3620, 95% CI -£7743 to £502). For the non-cardiac surgery stratum, mean costs were lower in the TGC than in the CM arm (incremental cost -£9865, 95% CI -£18,558 to -£1172), but, in the cardiac surgery stratum, the costs were similar between the arms (incremental cost £133, 95% CI -£3568 to £3833). Lifetime incremental net benefits were positive overall (£3346, 95% CI -£11,203 to £17,894), but close to zero for the cardiac surgery stratum (-£919, 95% CI -£16,661 to £14,823). For the non-cardiac surgery stratum, the incremental net benefits were high (£11,322, 95% CI -£15,791 to £38,615). The probability that TGC is cost-effective is relatively high for the non-cardiac surgery stratum, but, for the cardiac surgery subgroup, the probability that TGC is cost-effective is around 0.5. Sensitivity analyses showed that the results were robust to a range of alternative assumptions. CONCLUSIONS: CHiP found no differences in the clinical or cost-effectiveness of TGC compared with CM overall, or for prespecified subgroups. A higher proportion of the TGC arm had hypoglycaemia. This study did not provide any evidence to suggest that PICUs should stop providing CM for children admitted to PICUs following cardiac surgery. For the subgroup not admitted for cardiac surgery, TGC reduced average costs at 12 months and is likely to be cost-effective. Further research is required to refine the TGC protocol to minimise the risk of hypoglycaemic episodes and assess the long-term health benefits of TGC. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61735247. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 26. See the NIHR Journals Library website for further project information.

Standard error estimation using the EM algorithm for the joint modeling of survival and longitudinal data.

Joint modeling of survival and longitudinal data has been studied extensively in the recent literature. The likelihood approach is one of the most popular estimation methods employed within the joint modeling framework. Typically, the parameters are estimated using maximum likelihood, with computation performed by the expectation maximization (EM) algorithm. However, one drawback of this approach is that standard error (SE) estimates are not automatically produced when using the EM algorithm. Many different procedures have been proposed to obtain the asymptotic covariance matrix for the parameters when the number of parameters is typically small. In the joint modeling context, however, there may be an infinite-dimensional parameter, the baseline hazard function, which greatly complicates the problem, so that the existing methods cannot be readily applied. The profile likelihood and the bootstrap methods overcome the difficulty to some extent; however, they can be computationally intensive. In this paper, we propose two new methods for SE estimation using the EM algorithm that allow for more efficient computation of the SE of a subset of parametric components in a semiparametric or high-dimensional parametric model. The precision and computation time are evaluated through a thorough simulation study. We conclude with an application of our SE estimation method to analyze an HIV clinical trial dataset.