Parenteral fluid regimens for improving functional outcome in acute stroke patients

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess whether different fluid regimens affect outcome in adult stroke patients.

Background

The World Health Organization (WHO) estimated that in 2002, 15.3 million strokes were reported worldwide, more than a third of which (five to six million) were fatal (WHO Geneva). Stroke is the second leading cause of death and the third leading cause of disability worldwide (Feigin 2005). Therefore, any small improvement in stroke management would benefit many people.

Fluids are a commonly used intervention in stroke patients who cannot swallow. Although swallow recovers in more than 80% of people within two to four weeks of stroke onset (Gordon 1987), in the immediate poststroke period, those with a poor swallow are at higher than average risk of dehydration.

Dehydration might worsen the ischaemic penumbra and influence stroke evolution in the acute phase (Britton 1980). Other complications associated with dehydration are infection, deep venous thrombosis, constipation and exacerbation of confusion (Finestone 2001; Kositzke 1990). Hence parenteral fluids are widely used. Giving intravenous saline to stroke patients who are hypotensive is said to improve their cerebral perfusion, although no direct evidence has shown that this improves outcome (Jauch 2013).

However, parenteral fluids may also lead to harm. Overhydration may lead to cerebral oedema, cardiac failure and hyponatraemia. Infection can develop around the sites of intravenous or subcutaneous catheters that can potentially lead to cellulitis or systemic infection. Indirect evidence that increased fluids might lead to harm comes from the Glucose Insulin in Stroke Trial (GIST) trial, in which people who received the greatest volumes of infusion had the worst outcomes (although this may well be confounded by baseline glucose levels) (Scott 1999). Evidence from other conditions suggests that lower replacement volumes may be beneficial, as in children with acute infection (Myburgh 2011) and in intensive care (Myburgh 2013). Furthermore, a sodium load with intravenous saline may lead to renal stress or hypertension (Myburgh 2013), and subcutaneous fluid regimens may not adequately replace potassium.

To date, no systematic reviews have examined different fluid regimens in acute stroke patients. One Cochrane review has explored haemodilution (Asplund 2002), although haemodilution regimens are not currently used in clinical practice.

Therefore, a systematic review is required to provide clear information on evidence related to the effects of different fluid regimens on important clinical outcomes in acute stroke patients. If strong evidence becomes available, it would assist healthcare professionals in better managing parenteral fluid in acute stroke patients, with an aim toward improving patient outcome. In the absence of adequate strong evidence, this review would highlight key uncertainties that are important for the development of future pragmatic clinical trials.

Description of the condition

Stroke was defined by the WHO in 1978 as a "neurological deficit of cerebrovascular cause that persists beyond 24 hours or is interrupted by death within 24 hours.". About 80% of strokes are ischaemic (caused by interruption of the blood supply to a particular area in the brain), and the remaining 20% are haemorrhagic (mainly due to an abnormal vascular structure or to rupture of a vessel) (Sims 2010). Subarachnoid haemorrhage has a different cause and prognosis from ischaemic and haemorrhagic strokes. Approximately 75% of stroke patients are left with an impairment encompassing physical, psychological and social domains (Reith 1997), whilst between 20% and 50% die within the first month, depending on the type and severity of the stroke, the age of the patient, co-morbidities and effectiveness of treatment for complications (Truelsen 2000).

Description of the intervention

Intravenous or subcutaneous fluids aim to prevent or correct problems associated with reduced intake of fluids. Previous recommendations (NICE 2013), which are not based on randomised evidence, have suggested that the weight of the individual, acid base and electrolyte disturbances and insensible losses are important factors when the volume and type of fluid therapy are targeted.

Several important aspects of parenteral fluid prescription have been identified.

  1. Type of fluid.

  2. Volume of fluid.

  3. Duration of fluid administration.

  4. Administration method used.

How the intervention might work

The outcome of the use of parenteral fluids in acute stroke patients depends on a multitude of factors, such as type, volume, duration and mode of delivery. Possible effects of each of these are summarised as follows.

  1. Type of fluid.

    1. Isotonic saline: sodium chloride 0.9%, one of the most commonly used intravenous fluids, distributes throughout the extracellular fluid compartment, with only 25% remaining in the intravascular compartment. Issues in its use for maintenance include its high sodium content, which could lead to water and salt retention.

    2. Glucose 5%: the fluid is distributed throughout total body water and is potentially a useful means of correcting or preventing simple dehydration. However, it can increase risks of hyponatraemia and hyperglycaemia in those with diabetes.

    3. Glucose saline: risk of hyponatraemia is associated with these solutions if given rapidly or in excess.

    4. Balanced crystalloid solutions: these have similar properties to 0.9% saline in terms of volume of distribution. However, because of the lower concentration of sodium, patients are likely to have a lesser chance of retaining sodium and water. These might be useful in maintenance regimens.

    5. Colloids (synthetic or albumin): these can expand intravascular volume better than crystalloids and provide an advantage in resuscitation. However, their cost, risk of anaphylactic reactions and association with renal function limit their use in resuscitation.

  2. Volume of fluid. Most authorities recommend a fixed dose of fluid for most patients that is targeted on the basis of renal impairment or judged hydration states. This may lead to potential harms, for example:

    1. more than required volume given could cause cerebral oedema, respiratory distress, cardiac failure and hyponatraemia; and

    2. less than required volume given could promote dehydration and associated complications of acute renal failure, deep venous thrombosis, confusion and infection.

  3. Duration of fluid administration.

    1. A longer period of fluid administration could lead to complications associated with overhydration and the mode used to administer such fluids.

    2. A shorter period of fluid administration could lead to complications associated with dehydration.

  4. Administration method used.

    1. Intravenous fluids have better penetration and blood volume expansion in comparison with subcutaneous fluids. However, a higher rate of infection might be due to the introduction of a needle into the bloodstream.

    2. Use of subcutaneous fluids might be easier and carries a lower infection risk. However, this practice limits the rate of fluid administration, can cause unsightly skin blebs and may lead to hypokalaemia.

Why it is important to do this review

The current National Institute for Health and Care Excellence (NICE) guideline (NICE 2013) for the use of intravenous fluids in medical patients highlights the lack of systematic reviews and clinical trials to guide fluid treatment of inpatients, including those who have sustained a stroke.

  1. "There is no RCT evidence found comparing fluid maintenance types."

  2. "No studies comparing the effect of different timings of starting, stopping or duration of IV fluid administration were found."

  3. "The quality of evidence related to the optimal volume of infusion for routine maintenance is variable."

  4. "The quality of evidence for outcomes analysed in systematic reviews found on the type, volume and timing of fluids to be used for resuscitation ranged from very low to high."

Therefore, it is important to do a systematic review to identify gaps in current understanding and knowledge gained about risks and benefits of parenteral fluids in stroke patients.

Objectives

To assess whether different fluid regimens affect outcome in adult stroke patients.

Methods

Criteria for considering studies for this review

Types of studies

We will consider all published and unpublished randomised controlled trials (RCTs) in which fluids have been used as an intervention to improve outcome in poststroke participants. We will also consider cluster-randomised trials. We will include trials with or without blinding of assessors, participants or both. We will exclude quasi-randomised, non-randomised and cross-over trials.

Types of participants

We will include trials of individuals who have had an acute disabling stroke (less than seven days after the event) in whom fluid therapy has been tested.

We aim to examine subgroups of patients by their ability to swallow, if these data are available.

We will include all adults (aged 18 years or older) of any gender or ethnicity after a stroke. We will use the WHO definition of stroke (Hatano 1976) and will include patients who have had an ischaemic or haemorrhagic stroke (but not a subarachnoid haemorrhage). We will include all types, severities and stages of stroke, and confirmation of the diagnosis using imaging is not compulsory. The diagnosis should be made by a doctor on either clinical or radiological grounds.

We will define dysphagic patients as those who have failed a formal swallow assessment performed by a nurse or a speech and language therapist.

This review will focus on the immediate period (within one week) post stroke; therefore we will include all inpatients and those cared for in a different setting (e.g. rehabilitation ward, community, nursing home) during that period.

We will consider the inclusion of studies in which only a subset of patients fit the inclusion criteria if an outcome measurement scale is included specifically for these patients.

Types of interventions

We will seek studies that have made the following comparisons.

  1. Type of fluid.

    1. Use of hypertonic fluids versus hypotonic fluids.

    2. Use of 0.9% saline versus other fluid types (e.g. colloids, other crystalloids).

  2. Volume of fluids.

    1. Greater versus lesser volume of fluid.

    2. Administration of a fixed volume versus a targeted volume.

  3. Duration of fluid administration.

    1. Continuously versus intermittently.

    2. Longer duration versus shorter duration.

  4. Administration method used.

    1. Intravenous versus subcutaneous.

We anticipate that studies of these comparisons will report variations in dosage or intensity, mode of delivery (intravenous versus subcutaneous), personnel who delivered it, frequency of delivery and duration and timing of delivery. We will collect data specifically to cover all of the above modalities and will plan to make comparisons between intervention groups. It is not possible, at this point in the review's development, to define thresholds for the comparison of more versus less fluid or the duration of treatment, as the standard volume or duration of treatment is not defined in current guidelines. We will document the regimen and delivery of the intervention and will contact study authors when this information is not clear.

Types of outcome measures

Our outcomes include death or dependence after stroke. In addition, we aim to measure potential harms of fluid therapies.

A number of scales have been used in stroke research to assess functional outcome post stroke (De Haan 1993); the most common is the modified Rankin Scale (mRS) (Banks 2007), which measures activity limitation and participation restriction. It has been published and validated.

This scale is interpreted as follows.

  1. Grade 0: no symptoms at all.

  2. Grade 1: no significant disability despite symptoms; ability to carry out all usual duties and activities.

  3. Grade 2: slight disability; inability to carry out all previous activities with ability to look after own affairs without assistance.

  4. Grade 3: moderate disability requiring some help but with ability to walk without assistance.

  5. Grade 4: moderately severe disability; inability to walk without assistance and inability to attend to own bodily needs.

  6. Grade 5: severe disability; state of being bedridden and incontinent and requiring constant nursing care and attention.

  7. Grade 6: death.

We anticipate that any studies identified may use the mRS scale to assess outcome post stroke. Other outcome scales include the Oxford Handicap Scale (Bamford 1989), the Barthel Index (Granger 1979), the Scandinavian Stroke Scale (SSSG) and the National Institutes of Health Stroke Scale (NIHSS) (Adams 1999). We plan to include studies that use these scales.

Primary outcomes

Independence post stroke at three to six months (measured as mRS grade 2 or less).

Secondary outcomes
  1. Death by three to six months (mRS 6).

  2. Complications, potentially attributable to fluid therapy, such as infection (pneumonia), cardiac failure, cerebral oedema and renal failure.

If we gather sufficient data, we may examine the following subgroups.

  1. Lesion type (i.e. ischaemic versus haemorrhagic).

  2. Ability to swallow.

Search methods for identification of studies

See the 'Specialized register' section in the Cochrane Stroke Group module. We will include trials in all languages and formats and will arrange translation of relevant papers published in languages other than English. We will adhere to copyright legislation and the terms of database licensing agreements.

Electronic searches

We will search the following electronic databases.

  1. Cochrane Stroke Group Trials Register.

  2. Cochrane Central Register of Controlled trials (CENTRAL) latest issue, part of The Cochrane Library.

  3. Cochrane Database of Systematic Reviews (CDSR) latest issue, part of The Cochrane Library.

  4. Database of Abstracts of Reviews of Effects (DARE) latest issue, part of The Cochrane Library.

  5. MEDLINE (Ovid) (1946 to present) (Appendix 1).

  6. EMBASE (Ovid) (1974 to present).

  7. CINAHL (EBSCO) (1982 to present).

We developed the MEDLINE search strategy (Appendix 1) in collaboration with the Cochrane Stroke Group Trials Search Co-ordinator and will adapt it to search the other databases.

In addition, we will search the following ongoing trials and research registers.

  1. Stroke Trials Registry (www.strokecenter.org/trials/).

  2. National Research Register Archive (https://portal.nihr.ac.uk/Pages/NRRArchiveSearch.aspx).

  3. ClinicalTrials.gov (http://clinicaltrials.gov/).

  4. Current Controlled Trials (www.controlledtrials.com).

Searching other resources

We will make efforts to identify further published, unpublished and ongoing trials by:

  1. searching reference lists from published reviews and relevant papers;

  2. using Science Citation Index Cited Reference Search for forward tracking of relevant papers; and

  3. contacting study authors and researchers active in the field.

Data collection and analysis

Selection of studies

We will manage all records identified from the electronic searches by using reference management software and will remove all duplicate records. One review author (AV) will screen titles and abstracts of references obtained as a result of our searching activities and will exclude obviously irrelevant papers. Two review authors (WW and AV) will retrieve full-text articles of the remaining references and will independently assess each study for inclusion in the review on the basis of eligibility criteria. We will identify and record the reasons for exclusion of ineligible studies. To avoid double counting of the same participants, if a study publishes data more than once, we will use the publication with the largest number of participants.

Both WW and AV will independently collect specific data, including names of study authors, specific details of interventions (e.g. dose, frequency), numbers of participants, date and duration of the study and results and will then apply the eligibility criteria to all of the studies screened.

Together, we will run a pilot test on a sample of reports (approximately 10 to 12 papers) to ensure consistency between review authors.

We will consult one review author (MD) to resolve disagreements on whether certain studies should be included.

We will record the selection process and will complete a PRISMA flow diagram.

Data extraction and management

We will use a predesigned data extraction form to extract data from studies that meet the inclusion criteria. Two review authors (WW and AV) will independently document the following information.

  1. Source of data, including study ID, report ID, review author ID and citation and contact details.

  2. Methods: study design, total study duration, method of randomisation, allocation concealment, risk of bias, blinding and follow-up.

  3. Participants: total number, setting, age, sex, type of stroke, method of stroke diagnosis, severity of disability recorded and assessment of swallow.

  4. Interventions: type of intervention post stroke, more versus less fluid, type of fluid given and duration and timing of fluids.

  5. Outcomes: primary and secondary outcomes relevant to this review as documented, as well as morbidity and mortality associated with the intervention and time to outcome measure.

  6. Miscellaneous: any funding source, references to other relevant studies and comments by review authors.

The review authors will resolve data extraction discrepancies through discussion. We will consult the third review author (MD) to resolve uncertainty or continued disagreement. We will manage extracted data by entering them directly into RevMan (RevMan 2012).

Assessment of risk of bias in included studies

Two review authors (AV and WW) will independently assess each included study using the tool for assessing risk of bias of The Cochrane Collaboration, as outlined in the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2011 ). We will extract data into risk of bias tables, where each entry will be graded as 'low risk,' 'high risk' or 'unclear risk.' The last category indicates lack of information or uncertainty over the potential for bias. We will create plots of risk of bias assessments using RevMan. As per the risk of bias tool, we will consider the following domains.

  1. Sequence generation (selection bias).

  2. Allocation sequence concealment (selection bias).

  3. Blinding of participants and personnel (performance bias).

  4. Blinding of outcome assessment (detection bias).

  5. Incomplete outcome data (attrition bias).

  6. Selective outcome reporting (reporting bias).

  7. Other potential sources of bias.

We will test assessments of the risk of bias within our review team on a pilot sample of three to six articles with varying range of bias to ensure that criteria are applied consistently and that a consensus is reached. We will discuss disagreements and, if necessary, will consult the third review author (MD) to achieve a consensus.

Measures of treatment effect

We will use RevMan 5.2 (RevMan 2012) to carry out statistical analyses to determine the intervention effect for each study included. We will use odds ratios (ORs) with 95% confidence intervals (CIs) to report results for dichotomous (binary) data.

Unit of analysis issues

We will take into account the level at which randomisation occurred in each study included. We will obtain study level data. We will examine outcomes at three to six months post stroke. We will analyse the outcomes of functional ability and death as dichotomous data. We will use 2 × 2 tables, with effects of the intervention expressed as risk ratios (RRs), ORs or risk differences (RDs). For cluster-randomised trials, we will aim to extract information that is a direct estimate of the required effect measure. We will seek advice from a statistician to ensure that the method used is appropriate.

Dealing with missing data

When possible, we will attempt to contact the original investigators to request missing data. We will not use replacement values in place of missing data.

Assessment of heterogeneity

We will use the I² statistic to measure heterogeneity among the trials in each analysis (Higgins 2003). We will consider values of 50% and above as representing significant heterogeneity. If this was the case, we will recheck our data to ensure that they have been correctly extracted and entered into RevMan. We will explore this heterogeneity by conducting preplanned subgroup analyses.

Assessment of reporting biases

We will carefully assess each included study for risk of bias as outlined above. We will attempt to avoid reporting bias by using a comprehensive search strategy as outlined above. This would involve searching relevant electronic sources and other trials registers. We will identify unpublished studies and will consider their inclusion. We will consider the use of funnel plots to investigate publication bias (Egger 1997).

Data synthesis

Our intention is to identify and collate all studies of parenteral fluid use (delivered using different modes, at varying timings, with different volumes and types) in acute stroke patients. Our aim is to investigate the effect of fluids on death or disability post stroke at three to six months.

Two review authors (AV and WW) will independently identify comparisons to be done and will discuss disagreements with the third review author (MD).

AV and WW will extract data from the included trials. AV will enter the data into RevMan 5.2 (RevMan 2012), and WW will check the entries. We will resolve through discussion disagreements that arise. When we consider studies sufficiently similar, we will conduct a meta-analysis by pooling the appropriate data using RevMan 5.2 (RevMan 2012).

We will construct forest plots to compare four intervention groups: type of fluid (saline versus others, hypertonic versus hypotonic), volume of fluid (more versus less, fixed versus targeted), duration of fluid administration (intermittent versus continuous, longer versus shorter) and mode of delivery (intravenous versus subcutaneous). We intend to analyse dichotomous outcome data. These data will be of the following form: functional impairment or death versus independence.

When making comparisons between 'more versus less' and 'longer versus shorter' fluid volume and duration, we will choose the most frequently used duration or volume as the reference for forest plots versus comparator regimens of more (or longer) fluids. If comparator regimens with more fluids and comparator regimens with less fluids are included, we will illustrate these comparators separately. We will consider more complex modelling, assuming a constant OR between increasing volume or time and death or dependence, if data are sufficient (more than five studies).

We will calculate intervention effects using a fixed-effect model and will report them as ORs with 95% CIs.

Subgroup analysis and investigation of heterogeneity

In addition to the overall analysis, if appropriate and sufficient data are available, we may perform separate analyses for the following subgroups.

  1. Different stroke type: ischaemic versus haemorrhagic.

  2. Ability to swallow.

As with the rest of the analysis, we will use the I² statistic to assess heterogeneity in our subgroups.

Sensitivity analysis

If results are not reported by stroke subtype or the ability to swallow, we will not perform a sensitivity analysis.

Acknowledgements

We would like to thank Mrs Brenda Thomas for her help in developing the MEDLINE search strategy.

Appendices

Appendix 1. MEDLINE search strategy

1. cerebrovascular disorders/ or exp basal ganglia cerebrovascular disease/ or exp brain ischemia/ or exp carotid artery diseases/ or exp cerebrovascular trauma/ or exp intracranial arterial diseases/ or exp intracranial arteriovenous malformations/ or exp "intracranial embolism and thrombosis"/ or exp intracranial hemorrhages/ or stroke/ or exp brain infarction/ or vasospasm, intracranial/ or brain injuries/
2. (stroke or poststroke or post-stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or apoplex$).tw.
3. ((brain$ or cerebr$ or cerebell$ or intracran$ or intracerebral) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$)).tw.
4. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracranial) adj5 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).tw.
5. brain injur$.tw.
6. 1 or 2 or 3 or 4 or 5
7. exp fluid therapy/ or exp water-electrolyte balance/th or water-electrolyte imbalance/th or dehydration/th
8. rehydration solutions/ or hypertonic solutions/ or glucose solution, hypertonic/ or saline solution, hypertonic/ or hypotonic solutions/ or isotonic solutions/
9. hydroxyethyl starch derivatives/ or albumins/ or exp serum albumin/ or exp colloids/ or exp dextrans/ or plasma substitutes/ or polygeline/ or povidone/ or glucose/
10. sodium bicarbonate/ or potassium chloride/ or sodium chloride/
11. exp *plasma/ or exp *serum/ or electrolytes/tu
12. ((fluid$ or volume or electrolyte$ or plasma) adj3 (therap$ or intravenous or IV or infusion$ or subcutaneous or drip or drips or administration or substitute$ or restor$ or resuscitat$ or replac$)).tw.
13. (rehydrate$ or hydrat$).tw.
14. ((blood or plasma) adj3 (substitut$ or expan$)).tw.
15. (colloid$ or hydrocolloid$ or crystalloid$ or albumin$ or albumen$ or hydroxyethylstarch$ or hydroxyethyl starch$ or dextran$ or gelofus$ or hemaccel$ or haemaccel$ or hetastarch or isotonic or hypertonic or hypotonic or ringer$ or gelatin$ or gentran$ or pentastarch$ or pentaspan$ or hartman$ or sodium chloride or potassium chloride or saline or glucose or dextrose or bicarbonate).ti.
16. ((colloid$ or hydrocolloid$ or crystalloid$ or albumin$ or albumen$ or hydroxyethylstarch$ or hydroxyethyl starch$ dextran$ or gelofus$ or hemaccel$ or haemaccel$ or serum or hetastarch or isotonic or hypertonic or hypotonic or ringer$ or gelatin$ or gentran$ or pentastarch$ or pentaspan$ or hartmann$ or sodium or potassium or saline or glucose or dextrose or bicarbonate) adj3 (solution$ or fluid$ or therap$ or intravenous or IV or infusion$ or subcutaneous or drip or drips or administration or substitute$ or restor$ or resuscitat$ or replac$)).tw.
17. infusions, parenteral/ or infusions, intravenous/ or exp infusions, subcutaneous/
18. (colloid$ or hydrocolloid$ or crystalloid$ or albumin$ or albumen$ or hydroxyethylstarch$ or hydroxyethyl starch$ or dextran$ or gelofus$ or hemaccel$ or haemaccel$ or serum or hetastarch or isotonic or hypertonic or hypotonic or ringer$ or gelatin$ or gentran$ or pentastarch$ or pentaspan$ or hartman$ or sodium or potassium or saline or glucose or dextrose or bicarbonate).tw.
19. 17 and 18
20. (volume adj3 expan$).tw.
21. ((balanced or physiologic$ or parenteral) adj3 (fluid$ or solution$)).tw.
22. ((fresh or frozen) adj3 plasma).tw.
23. 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 19 or 20 or 21 or 22
24. Randomized Controlled Trials as Topic/
25. random allocation/
26. Controlled Clinical Trials as Topic/
27. control groups/
28. clinical trials as topic/ or clinical trials, phase i as topic/ or clinical trials, phase ii as topic/ or clinical trials, phase iii as topic/ or clinical trials, phase iv as topic/
29. double-blind method/
30. single-blind method/
31. Placebos/
32. placebo effect/
33. cross-over studies/
34. Therapies, Investigational/
35. Research Design/
36. randomized controlled trial.pt.
37. controlled clinical trial.pt.
38. (clinical trial or clinical trial phase i or clinical trial phase ii or clinical trial phase iii or clinical trial phase iv).pt.
39. (random$ or RCT or RCTs).tw.
40. (controlled adj5 (trial$ or stud$)).tw.
41. (clinical$ adj5 trial$).tw.
42. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw.
43. (quasi-random$ or quasi random$ or pseudo-random$ or pseudo random$).tw.
44. ((control or experiment$ or conservative) adj5 (treatment or therapy or procedure or manage$)).tw.
45. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw.
46. (cross-over or cross over or crossover).tw.
47. (placebo$ or sham).tw.
48. trial.ti.
49. (assign$ or allocat$).tw.
50. controls.tw.
51. or/24-50
52. 6 and 23 and 51
53. exp animals/ not humans.sh.
54. 52 not 53
55. (neonat$ or newborn$ or new born or pediatric or paediatric or birth or infant or infants or perinatal or peri-natal or baby or babies or child or children).ti.
56. 54 not 55

Contributions of authors

As listed in individual sections above.

Declarations of interest

None known.

Ancillary