The implausibility of ‘usual care’ in an open system: sedation and weaning practices in Paediatric Intensive Care Units (PICUs) in the United Kingdom (UK).

Background
The power of the randomised controlled trial depends upon its capacity to operate in a closed system whereby the intervention is the only causal force acting upon the experimental group and absent in the control group, permitting a valid assessment of intervention efficacy. Conversely, clinical arenas are open systems where factors relating to context, resources, interpretation and actions of individuals will affect implementation and effectiveness of interventions. Consequently, the comparator (usual care) can be difficult to define and variable in multi-centre trials. Hence outcomes cannot be understood without considering usual care and factors that may affect implementation and impact on the intervention.

Methods
Using a fieldwork approach, we describe PICU context, ‘usual’ practice in sedation and weaning from mechanical ventilation, and factors affecting implementation prior to designing a trial involving a sedation and ventilation weaning intervention. We collected data from 23 UK PICUs between June and November 2014 using observation, individual and multi-disciplinary group interviews with staff.

Results
Pain and sedation practices were broadly similar in terms of drug usage and assessment tools. Sedation protocols linking assessment to appropriate titration of sedatives and sedation holds were rarely used (9 % and 4 % of PICUs respectively). Ventilator weaning was primarily a medical-led process with 39 % of PICUs engaging senior nurses in the process: weaning protocols were rarely used (9 % of PICUs). Weaning methods were variably based on clinician preference. No formal criteria or use of spontaneous breathing trials were used to test weaning readiness. Seventeen PICUs (74 %) had prior engagement in multi-centre trials, but limited research nurse availability. Barriers to previous trial implementation were intervention complexity, lack of belief in the evidence and inadequate training. Facilitating factors were senior staff buy-in and dedicated research nurse provision.

Conclusions
We examined and identified contextual and organisational factors that may impact on the implementation of our intervention. We found usual practice relating to sedation, analgesia and ventilator weaning broadly similar, yet distinctively different from our proposed intervention, providing assurance in our ability to evaluate intervention effects. The data will enable us to develop an implementation plan; considering these factors we can more fully understand their impact on study outcomes.

Parents’ and young people’s involvement in designing a trial of ventilator weaning

Consulting with users is considered best practice and is highly recommended in designing new trials. As part of our feasibility work, we undertook a consultation exercise with parents, ex-patients and young people prior to designing a trial of protocol-based ventilator weaning. Our aims were to (1) ascertain views on the relevance and importance of the trial; (2) determine the important parent/patient outcome measures; and (3) ascertain views on informed consent in a cluster randomized controlled trial. We conducted audio-recorded face-to-face, telephone and focus group interviews with parents and young people. Data were content analysed to generate information to address our specific consultation objectives. The setting was the north-western region of England. A total of 16 participants were interviewed: 2 parents of paediatric intensive care unit (PICU) survivors; 1 PICU survivor; and 13 young people from the former Medicines for Children Research Network. The trial objectives were deemed important and relevant, and participants considered the most important outcome measure to be the length of time on ventilation. Parents and young people did not consider written informed consent to be a necessary requirement in the context of this trial, rather awareness of unit participation in the trial was important with the opportunity of opting out of data collection. This consultation provided useful, pragmatic insights to inform trial design. We encountered significant challenges in recruiting parents and young people for this consultation exercise, and novel recruitment methods need to be considered for future work in this field. Patient and public involvement is essential to ensure that future trials answer parent-relevant questions and have meaningful outcome measures, as well as involving parents and young people in the general development of health care services.

Factors that impact on the use of mechanical ventilation weaning protocols in critically ill adults and children: a qualitative-evidence synthesis

Background:
Prolonged mechanical ventilation is associated with a longer intensive care unit (ICU) length of stay and higher mortality. Consequently, methods to improve ventilator weaning processes have been sought. Two recent Cochrane systematic reviews in ICU adult and paediatric populations concluded that protocols can be effective in reducing the duration of mechanical ventilation, but there was significant heterogeneity in study findings. Growing awareness of the benefits of understanding the contextual factors impacting on effectiveness has encouraged the integration of qualitative evidence syntheses with effectiveness reviews, which has delivered important insights into the reasons underpinning (differential) effectiveness of healthcare interventions.

Objectives:
1. To locate, appraise and synthesize qualitative evidence concerning the barriers and facilitators of the use of protocols for weaning critically-ill adults and children from mechanical ventilation;

2. To integrate this synthesis with two Cochrane effectiveness reviews of protocolized weaning to help explain observed heterogeneity by identifying contextual factors that impact on the use of protocols for weaning critically-ill adults and children from mechanical ventilation;

3. To use the integrated body of evidence to suggest the circumstances in which weaning protocols are most likely to be used.

Search methods:
We used a range of search terms identified with the help of the SPICE (Setting, Perspective, Intervention, Comparison, Evaluation) mnemonic. Where available, we used appropriate methodological filters for specific databases. We searched the following databases: Ovid MEDLINE, Embase, OVID, PsycINFO, CINAHL Plus, EBSCOHost, Web of Science Core Collection, ASSIA, IBSS, Sociological Abstracts, ProQuest and LILACS on the 26th February 2015. In addition, we searched: the grey literature; the websites of professional associations for relevant publications; and the reference lists of all publications reviewed. We also contacted authors of the trials included in the effectiveness reviews as well as of studies (potentially) included in the qualitative synthesis, conducted citation searches of the publications reporting these studies, and contacted content experts.

We reran the search on 3rd July 2016 and found three studies, which are awaiting classification.

Selection criteria:
We included qualitative studies that described: the circumstances in which protocols are designed, implemented or used, or both, and the views and experiences of healthcare professionals either involved in the design, implementation or use of weaning protocols or involved in the weaning of critically-ill adults and children from mechanical ventilation not using protocols. We included studies that: reflected on any aspect of the use of protocols, explored contextual factors relevant to the development, implementation or use of weaning protocols, and reported contextual phenomena and outcomes identified as relevant to the effectiveness of protocolized weaning from mechanical ventilation.

Data collection and analysis:
At each stage, two review authors undertook designated tasks, with the results shared amongst the wider team for discussion and final development. We independently reviewed all retrieved titles, abstracts and full papers for inclusion, and independently extracted selected data from included studies. We used the findings of the included studies to develop a new set of analytic themes focused on the barriers and facilitators to the use of protocols, and further refined them to produce a set of summary statements. We used the Confidence in the Evidence from Reviews of Qualitative Research (CERQual) framework to arrive at a final assessment of the overall confidence of the evidence used in the synthesis. We included all studies but undertook two sensitivity analyses to determine how the removal of certain bodies of evidence impacted on the content and confidence of the synthesis. We deployed a logic model to integrate the findings of the qualitative evidence synthesis with those of the Cochrane effectiveness reviews.

Main results:
We included 11 studies in our synthesis, involving 267 participants (one study did not report the number of participants). Five more studies are awaiting classification and will be dealt with when we update the review.

The quality of the evidence was mixed; of the 35 summary statements, we assessed 17 as ‘low’, 13 as ‘moderate’ and five as ‘high’ confidence. Our synthesis produced nine analytical themes, which report potential barriers and facilitators to the use of protocols. The themes are: the need for continual staff training and development; clinical experience as this promotes felt and perceived competence and confidence to wean; the vulnerability of weaning to disparate interprofessional working; an understanding of protocols as militating against a necessary proactivity in clinical practice; perceived nursing scope of practice and professional risk; ICU structure and processes of care; the ability of protocols to act as a prompt for shared care and consistency in weaning practice; maximizing the use of protocols through visibility and ease of implementation; and the ability of protocols to act as a framework for communication with parents.

Authors' conclusions:
There is a clear need for weaning protocols to take account of the social and cultural environment in which they are to be implemented. Irrespective of its inherent strengths, a protocol will not be used if it does not accommodate these complexities. In terms of protocol development, comprehensive interprofessional input will help to ensure broad-based understanding and a sense of ‘ownership’. In terms of implementation, all relevant ICU staff will benefit from general weaning as well as protocol-specific training; not only will this help secure a relevant clinical knowledge base and operational understanding, but will also demonstrate to others that this knowledge and understanding is in place. In order to maximize relevance and acceptability, protocols should be designed with the patient profile and requirements of the target ICU in mind. Predictably, an under-resourced ICU will impact adversely on protocol implementation, as staff will prioritize management of acutely deteriorating and critically-ill patients.

Protocolized versus non-protocolized weaning for reducing the duration of invasive mechanical ventilation in newborn infants: review

Background
Mechanical ventilation is a life-saving intervention for critically ill newborn infants with respiratory failure admitted to a neonatal intensive care unit (NICU). Ventilating newborn infants can be challenging due to small tidal volumes, high breathing frequencies, and the use of uncuffed endotracheal tubes. Mechanical ventilation has several short-term, as well as long-term complications. To prevent complications, weaning from the ventilator is started as soon as possible. Weaning aims to support the transfer from full mechanical ventilation support to spontaneous breathing activity.

Objectives
To assess the efficacy of protocolized versus non-protocolized ventilator weaning for newborn infants in reducing the duration of invasive mechanical ventilation, the duration of weaning, and shortening the NICU and hospital length of stay. To determine efficacy in predefined subgroups including: gestational age and birth weight; type of protocol; and type of protocol delivery. To establish whether protocolized weaning is safe and clinically effective in reducing the duration of mechanical ventilation without increasing the risk of adverse events.

Search methods
We searched the Cochrane Central Register of Controlled trials (CENTRAL; the Cochrane Library; 2015, Issue 7); MEDLINE In-Process and other Non-Indexed Citations and OVID MEDLINE (1950 to 31 July 2015); CINAHL (1982 to 31 July 2015); EMBASE (1988 to 31 July 2015); and Web of Science (1990 to 15 July 2015). We did not restrict language of publication. We contacted authors of studies with a subgroup of newborn infants in their study, and experts in the field regarding this subject. In addition, we searched abstracts from conference proceedings, theses, dissertations, and reference lists of all identified studies for further relevant studies.

Selection criteria
Randomized, quasi-randomized or cluster-randomized controlled trials that compared protocolized with non-protocolized ventilator weaning practices in newborn infants with a gestational age of 24 weeks or more, who were enrolled in the study before the postnatal age of 28 completed days after the expected date of birth.

Data collection and analysis
Four authors, in pairs, independently reviewed titles and abstracts identified by electronic searches. We retrieved full-text versions of potentially relevant studies.

Main results
Our search yielded 1752 records. We removed duplicates (1062) and irrelevant studies (843). We did not find any randomized, quasi-randomized or cluster-randomized controlled trials conducted on weaning from mechanical ventilation in newborn infants. Two randomized controlled trials met the inclusion criteria on type of study and type of intervention, but only included a proportion of newborns. The study authors could not provide data needed for subgroup analysis; we excluded both studies.

Authors' conclusions
Based on the results of this review, there is no evidence to support or refute the superiority or inferiority of weaning by protocol over non-protocol weaning on duration of invasive mechanical ventilation in newborn infants.

Weaning

There is no RIGHT time to wean your baby from the breast. Family, friends, health professionals and even strangers might try to give you many reasons to stop nursing your baby, but the decision should depend on what you and your baby need and want. Get thoughts from people who know about breastfeeding and decide what is best for YOU and YOUR baby.

Effect of within-litter birth weight variation on piglet survival and pre-weaning weight gain in a commercial herd

There are several factors that affect piglet survival and this has a bearing on sow productivity. Ten variables that influence pre-weaning vitality were analysed using records from the Pig Industry Board, Zimbabwe. These included individual piglet birth weight, piglet origin (nursed in original litter or fostered), sex, relative birth weight expressed as standard deviation units, sow parity, total number of piglets born, year and month of farrowing, within-litter variability and the presence of stillborn or mummified littermates. The main factors that influenced piglet mortality were fostering, parity and within-litter variability especially the weight of the individual piglet relative to the average of the litter (P<0.05). Presence of a mummified or stillborn littermate, which could be a proxy for unfavourable uterine environment or trauma during the birth process, did not influence pre-weaning mortality. Variability within a litter and the deviation of the weight of an individual piglet from the litter mean, influenced survival to weaning. It is, therefore, advisable for breeders to include uniformity within the litter as a selection criterion. The recording of various variables by farmers seems to be a useful management practice to identify piglets at risk so as to establish palliative measures. Further, farmers should know which litters and which piglets within a litter are at risk and require more attention.

Weaning preterm infants: a randomised controlled trial

Objective: To assess the effect on growth and iron status in preterm infants of a specially devised weaning strategy compared with current best practices in infant feeding. The preterm weaning strategy recommended the early onset of weaning and the use of foods with a higher energy and protein content than standard milk formula, and foods that are rich sources of iron and zinc. Subjects and design: In a blinded, controlled study, 68 preterm infants (mean (SD) birth weight 1470 (430) g and mean (SD) gestational age 31.3 (2.9) weeks) were randomised to either the preterm weaning strategy group (n = 37) or a current best practice control group (n = 31), from hospital discharge until 1 year gestation corrected age (GCA). Main outcome measures: Weight, supine length, occipitofrontal head circumference, and intakes of energy, protein, and minerals were determined at 0, 6, and 12 months GCA. Levels of haemoglobin, serum iron, and serum ferritin were assayed at 0 and 6 months GCA. Results: Significant positive effects of treatment included: greater increase in standard deviation length scores and length growth velocity; increased intake of energy, protein, and carbohydrate at 6 months GCA and iron at 12 months GCA; increased haemoglobin and serum iron levels at 6 months GCA. Conclusions: The preterm weaning strategy significantly influenced dietary intakes with consequent beneficial effects on growth in length and iron status. This strategy should be adopted as the basis of feeding guidelines for preterm infants after hospital discharge. School of Applied Statistics Faculty of Life Sciences

Weaning diet induces sustained metabolic phenotype shift in the pig and influences host response to Bifidobacterium lactis NCC2818

Background The process of weaning causes a major shift in intestinal microbiota and is a critical period for developing appropriate immune responses in young mammals.Objective To use a new systems approach to provide an overview of host metabolism and the developing immune system in response to nutritional intervention around the weaning period.Design Piglets (n=14) were weaned onto either an egg-based or soya-based diet at 3 weeks until 7 weeks, when all piglets were switched onto a fish-based diet. Half the animals on each weaning diet received Bifidobacterium lactis NCC2818 supplementation from weaning onwards. Immunoglobulin production from immunologically relevant intestinal sites was quantified and the urinary (1)H NMR metabolic profile was obtained from each animal at post mortem (11 weeks).Results Different weaning diets induced divergent and sustained shifts in the metabolic phenotype, which resulted in the alteration of urinary gut microbial co-metabolites, even after 4 weeks of dietary standardisation. B lactis NCC2818 supplementation affected the systemic metabolism of the different weaning diet groups over and above the effects of diet. Additionally, production of gut mucosa-associated IgA and IgM was found to depend upon the weaning diet and on B lactis NCC2818 supplementation.ConclusionThe correlation of urinary (1)H NMR metabolic profile with mucosal immunoglobulin production was demonstrated, thus confirming the value of this multi-platform approach in uncovering non-invasive biomarkers of immunity. This has clear potential for translation into human healthcare with the development of urine testing as a means of assessing mucosal immune status. This might lead to early diagnosis of intestinal dysbiosis and with subsequent intervention, arrest disease development. This system enhances our overall understanding of pathologies under supra-organismal control.

Dietary supplementation with Bifidobacterium lactis NCC2818 from weaning reduces local immunoglobulin production in lymphoid-associated tissues but increases systemic antibodies in healthy neonates

Weaning is associated with a major shift in the microbial community of the intestine, and this instability may make it more acquiescent than the adult microbiota to long-term changes. Modulation achieved through dietary interventions may have potentially beneficial effects on the developing immune system, which is driven primarily by the microbiota. The specific aim of the present study was to determine whether immune development could be modified by dietary supplementation with the human probiotic Bifidobacterium lactis NCC2818 in a tractable model of weaning in infants. Piglets were reared by their mothers before being weaned onto a solid diet supplemented with B. lactis NCC2818, while sibling controls did not receive supplementation. Probiotic supplementation resulted in a reduction in IgA (P,0·0005) and IgM (P,0·009) production by mucosal tissues but had no effect on IgG production (P.0·05). Probiotic- supplemented pigs had more mast cells than unsupplemented littermates (P,0·0001), although numbers in both groups were low. In addition, the supplemented piglets made stronger serum IgG responses to fed and injected antigens (P,0·05). The present findings are consistent with B. lactis NCC2818 reducing intestinal permeability induced by weaning, and suggest that the piglet is a valuable intermediate between rodent models and human infants. The results also strongly suggest that measures of the effect of probiotic supplementation on the immune system need to be interpreted carefully as proxy measures of health benefit. However, they are useful in developing an understanding of the mechanism of action of probiotic strains, an important factor in predicting favourable health outcomes of nutritional intervention.