Patient and public involvement in Paediatric Intensive Care research: considerations, challenges and facilitating factors.

PLAIN ENGLISH SUMMARY: Paediatric Intensive Care (PIC) provides care to extremely ill children. Research in this area can be difficult because children are often too sick to discuss being involved in a study and parents are too upset about their child to think about taking part. This makes it even more important that research is well designed. We conducted a review of the literature about involving patients and the public (PPI) in PIC research. We wanted to know what PPI has taken place, who had been consulted and how this was undertaken. We reviewed the titles and abstracts of 4717 papers but found only 4 relevant papers. Three of the papers had consulted with parents of children who had been on PIC but only one study had spoken directly to a child themselves. The studies had used a number of different methods to invite people to take part but there did not appear to be one solution. All of the studies thought PPI was good for the development of their research but none of them had tried to measure what had changed as a result. There are difficulties associated with carrying out PPI in the PIC setting. Researchers need to share more of their experiences, positive and negative, so we can try to identify the best ways of carrying out PPI in PIC studies. This will help ensure that research studies are designed which address the needs and concerns of children and their parents. ABSTRACT: Introduction Involving the public in health care research is reported to enhance the quality, appropriateness, acceptability and relevance to patients and the public (INVOLVE, Briefing notes for researchers, 2012; Staniszewska et al., Int J Technol Assess Health Care 274:391-9, 2011). Conducting research with children and young people is regarded as challenging and this makes it even more important that the research is well designed and understands the perspective of the child and family. We conducted a narrative literature review of the Patient and Public Involvement (PPI) literature, in the context of Paediatric Intensive Care (PIC). Our aims were to identify what PPI activity has taken place, with whom researchers engaged and what outcomes they reported. Method Electronic databases Medline, CINAHL and Embase (January 2000- June 2016) were searched using the search terms patient and public involvement and consultation. Participants were defined as child, parent, paediatric or pediatric and the context as intensive or critical care. Papers were excluded where activity reflected 'participants' as research subjects. Included papers were reviewed using the GRIPP checklist to appraise the quality of reporting. Results The search strategy identified 4717 abstracts. Seventeen papers were reviewed in full and four papers were included, all of which are case studies, describing a consultation approach. None of the papers described PPI as a multi-stage process. Only one study engaged with a former PIC patient and the majority of those consulted did not have any PIC experience. Activity was reported as being of benefit but there was no measurement of the impact of PPI. Conclusion There are numerous challenges associated with the conduct of research in PIC. It is therefore essential that the perspective of children, young people and their parents have been considered in the design of trials. However, there are few published accounts of PPI within the PIC context and the accounts that exist highlight issues about who to approach and when, and a lack of clarity about the best ways to engage with them. Research Ethics Committees and funding bodies expect to see evidence of PPI in research applications and we need to develop our understanding of what contributes towards successful PPI in this context.

Observational study of children admitted to United Kingdom and Republic of Ireland Paediatric Intensive Care Units after out-of-hospital cardiac arrest.

AIMS: To estimate the prevalence of children admitted after out-of-hospital cardiac arrest (OHCA) to UK and Republic of Ireland (RoI) Paediatric Intensive Care Units (PICUs) and factors associated with mortality to inform future clinical trial feasibility. METHOD: Observational study using a prospectively collected dataset of the Paediatric Intensive Care Audit Network (PICANet) of 33 UK and RoI PICUs (January 2003 to June 2010). Cases (0 to <16 years), with documented OHCA surviving to PICU admission and requiring mechanical ventilation were included. Main outcomes were prevalence for admission and death within PICU. Factors associated with mortality were examined with multiple logistic regression analysis. RESULTS: 827 of 111,170 admissions (0.73%; 95% CI [0.48 to 0.98%]) were identified as children admitted following OHCA. PICU mortality for OHCA was 50.5% (418/827). Recruitment into an adequately sized clinical trial would not be feasible with the current prevalence rate. Characteristics at PICU admission associated with increased risk of death included; bilateral unreactive pupils, genetically inherited condition, inter-hospital transfer to PICU, requirement for vasoactive drugs and greater base deficit. Factors associated with reduced risk of death were submersion or a respiratory aetiology and pre-existing respiratory or cardiac conditions. CONCLUSIONS: Less than 120 children a year are admitted to PICUs in the UK and RoI after OHCA, limiting options for conducting UK intervention trials. The risk factors associated with mortality identified in this study will allow risk stratification in future studies.

Severe head injury in children: emergency access to neurosurgery in the United Kingdom.

OBJECTIVE: To determine the scale of acute neurosurgery for severe traumatic brain injury (TBI) in childhood, and whether surgical evacuation for haematoma is achieved within four hours of presentation to an emergency department. METHODS: A 12 month audit of emergency access to all specialist neurosurgical and intensive care services in the UK. Severe TBI in a child was defined as that necessitating admission to intensive care. RESULTS: Of 448 children with severe head injuries, 91 (20.3%) underwent emergency neurosurgery, and 37% of these surgical patients had at least one non-reactive and dilated pupil. An acute subdural or epidural haematoma was present in 143/448 (31.9%) children, of whom 66 (46.2%) underwent surgery. Children needing surgical evacuation of haematoma were at a median distance of 29 km (interquartile range (IQR) 11.8-45.7) from their neurosurgical centre. One in four children took longer than one hour to reach hospital after injury. Once in an accident and emergency department, 41% took longer than fours hours to arrive at the regional centre. The median interval between time of accident and arrival at the surgical centre was 4.5 hours (IQR 2.23-7.73), and 79% of inter-hospital transfers were undertaken by the referring hospital rather than the regional centre. In cases where the regional centre undertook the transfer, none were completed within four hours of presentation-the median interval was 6.3 hours (IQR 5.1-8.12). CONCLUSIONS: The system of care for severely head injured children in the UK does not achieve surgical evacuation of a significant haematoma within four hours. The recommendation to use specialist regional paediatric transfer teams delays rather than expedites the emergency service.

Epidemiology of traumatic brain injury in children receiving intensive care in the UK.

AIMS: To describe the epidemiology of children with traumatic brain injury (TBI) admitted to paediatric intensive care units (PICUs) in the UK. METHODS: Prospective collection of clinical and demographic information from paediatric and adult intensive care units in the UK and Eire between February 2001 and August 2003. RESULTS: The UK prevalence rate for children (0-14 years) admitted to intensive care with TBI between February 2001 and August 2003 was 5.6 per 100,000 population per year (95% Poisson exact confidence intervals 5.17 to 6.05). Children admitted to PICUs with TBI were more deprived than the population as a whole (mean Townsend score for TBI admissions 1.19 v 0). The commonest mechanism of injury was a pedestrian accident (36%), most often occurring in children over 10. There was a significant summer peak in admissions in children under 10 years. Time of injury peaked in the late afternoon and early evening, a pattern that remained constant across the days of the week. Injuries involving motor vehicles have the highest mortality rates (23% of vehicle occupants, 12% of pedestrians) compared with cyclists (8%) and falls (3%). In two thirds of admissions (65%) TBI was an isolated injury. CONCLUSIONS: TBI in children requiring intensive care is more common in those from poorer backgrounds who have been involved in accidents as pedestrians. The summer peak in injury occurrence for 0-10 year olds and late afternoon timing give clear targets for community based injury prevention.

A new formula for blood transfusion volume in the critically ill.

BACKGROUND: Published formulae, frequently used to predict the volume of transfused red cells required to achieve a desired rise in haemoglobin (Hb) or haematocrit (Hct), do not appear to have been validated in clinical practice. AIMS: To examine the relation between transfusion volume and the resulting rise in Hb and Hct in critically ill children. METHODS: Phase 1: Sample of 50% of children admitted during 1997; 237 of these 495 patients received at least one packed red cell transfusion; 82 children were transfused without confounding factors that could influence the Hb/Hct response to transfusion and were analysed further. Actual rise in Hb concentration or haematocrit was compared to that expected from use of existing formulae. A new formula was developed. Phase 2: In 50 children receiving a packed red cell transfusion during 2001, actual rise in Hb concentration was compared to expected rise in Hb with use of the new formula. RESULTS: Phase 1: Existing formulae performed poorly; median ratio of actual/predicted rise in Hb or Hct ranged from 0.61 to 0.85. Using the regression coefficients new formulae were developed for both Hb and Hct. These formulae were applicable across all age and diagnostic groups. Phase 2: Median ratio of actual/predicted rise in Hb improved to 0.95 with use of the new formula. CONCLUSIONS: Existing formulae underestimate the volume of packed red cells required to achieve a target Hb or Hct. Adoption of the new formulae could reduce the number of transfusion episodes in PICU, cutting costs and reducing risk.

Distribution of pulmonary blood flow in the perfluorocarbon-filled lung.

OBJECTIVE: Partial liquid ventilation (PLV) improves gas exchange in animal studies of lung injury. Perfluorocarbons (PFCs) are heavy liquids and are therefore preferentially delivered to the most dependent areas of lung. We hypothesised that improved oxygenation during PLV might be the consequence of a redistribution of pulmonary blood flow away from poorly ventilated, dependent alveoli, leading to improved ventilation/perfusion (V/Q) matching. This study investigated whether partially filling the lung with PFC would result in a redistribution of pulmonary blood flow. DESIGN: Prospective experimental study. SETTING: Hospital research institute laboratory. PARTICIPANTS: Six anaesthetised pigs without lung injury. INTERVENTIONS: Animals were anaesthetised and ventilated (gas tidal volume 12 ml/kg, PEEP 5, FIO2 1.0, rate 16). Whilst the pigs were maintained in the supine position, regional pulmonary blood flow was measured during conventional gas ventilation and repeated during PLV. Flow to regions of lung was determined by injection of radioactive microspheres (Co(57), Sn(113), Sc(46)). Measurements were performed with ventilation held at end-expiratory pressure and, in two PLV animals only, repeated with ventilation held at peak inspiratory pressure. RESULTS: During conventional gas ventilation, blood flow followed a linear distribution with the highest flow to the most dependent lung. In the lung partially filled with PFC a diversion of blood flow away from the most dependent lung was seen (p = 0.007), resulting in a more uniform distribution of flow down the lung (p = 0.006). Linear regression analysis (r2 = 0.75) also confirmed a difference in distribution pattern. On applying an inspiratory hold to the liquid-containing lung, blood flow was redistributed back towards the dependent lung. CONCLUSIONS: Partially filling the lung with PFC results in a redistribution of pulmonary blood flow away from the dependent region of the lung. During PLV a different blood flow distribution may be seen between inspiration and expiration. The clinical significance of these findings has yet to be determined.

Renovascular and growth effects of childhood sarcoid.

A boy developed early onset sarcoidosis, an extremely rare mimic of juvenile chronic arthritis. Renal granulomas caused severe hypertension and renal impairment, which was controlled by azathioprine and steroids. Severe uveitis caused visual impairment. Impaired growth and delayed puberty, not previously described in childhood sarcoidosis, required growth hormone and testosterone treatment.

Cardiovascular abnormalities in end stage renal failure: the effect of anaemia or uraemia?

Children with end stage renal failure and anaemia have an increased cardiac index and often gross ventricular hypertrophy. Correction of anaemia with recombinant human erythropoietin (r-HuEpo) for less than six months results in a reduction in the cardiac index without a significant reduction in left ventricular hypertrophy. Seven children receiving dialysis (group 1) were studied to determine whether a reduction in left ventricular hypertrophy would occur after a 12 month period of r-HuEpo. A decrease in the cardiac index was seen by six months, and a significant reduction in left ventricular mass index and cardiothoracic ratio was seen by 12 months. Successful renal transplantation also results in a reduction in the cardiac index and left ventricular hypertrophy, but the relative contributions of correction of anaemia and correction of biochemical disturbance is unknown because they usually improve simultaneously. To investigate this, six children (group 2) who already had a mean haemoglobin concentration of 107 g/l while receiving dialysis were followed up for 12 months after successful transplantation. They showed no significant change in haemoglobin concentration, but a dramatic improvement in biochemistry. There was no significant change in cardiovascular function. Anaemia is the more dominant influence on cardiovascular function in end stage renal failure.

Assessing iron status in children with chronic renal failure on erythropoietin: which measurements should we use?

Iron deficiency severely limits the efficacy of recombinant human erythropoietin (EPO). In order to determine how best to identify and monitor children at risk of developing iron deficiency, we serially measured several parameters of iron status in nine children before and during a 24-week period of EPO therapy. Serum ferritin was the best predictor of development of iron deficiency, five of the nine children developed iron deficiency, characterised by a poor haemoglobin response or evidence of microcytosis and hypochromia; all had a serum ferritin of 60 micrograms/l or less at the start of EPO. Haemoglobin response was also related to change in mean red cell volume (MCV); a falling MCV, irrespective of absolute value, accompanying a poor response to EPO. Iron treatment in five children resulted in significant improvements in haemoglobin and iron status parameters. Although MCV remained low, there was a marked increase in red cell volume distribution width after iron, which may be of value in monitoring the response to iron therapy. We suggest that children with a serum ferritin of 60 micrograms/l or less and those who develop a falling MCV during EPO treatment should receive high-dose oral iron supplementation before and during treatment with EPO.

Pain after subcutaneous injection of recombinant human erythropoietin: does Emla cream help?

Recombinant human erythropoietin (rHuEpo) is used to correct anaemia in dialysis patients. Subcutaneous administration of rHuEpo may be associated with pain at the injection site. This study assessed the pain of subcutaneous infiltration of two different preparations of rHuEpo, alpha and beta, and the value of a local anaesthetic (Emla) cream, in reducing the pain of infiltration. Forty-eight haemodialysis patients were enrolled into a double-blind, placebo-controlled, paired-comparison study. Pain was assessed using a visual analogue scale, a verbal descriptive scale and a direct comparison between paired treatments. Subcutaneous injection of rHuEpo alpha was more painful than rHuEpo beta (P < 0.001); using placebo cream 42% of patients described the pain of rHuEpo alpha as severe or very severe, whereas none of the patients found rHuEpo beta so painful. Application of Emla for at least 2 h prior to injection resulted in a significant reduction in the pain of both preparations, but was unable to reduce the pain of rHuEpo alpha to that of rHuEpo beta. Subcutaneous injection of rHuEpo alpha is more painful than rHuEpo beta, even after application of Emla. Although the discomfort of rHuEpo beta is graded as very mild by most adult patients the use of Emla is associated with a significant reduction in discomfort, which may be of benefit to paediatric patients.

Non-cardiac benefits of human recombinant erythropoietin in end stage renal failure and anaemia.

Recombinant human erythropoietin (r-HuEpo) is now available to correct the anaemia of end stage renal failure. The clinical consequences of increasing the haemoglobin concentration in children on dialysis are incompletely documented; a placebo controlled study is essential when assessing subjective changes, for example in appetite or other aspects of quality of life. A single blind, placebo controlled crossover study in 11 children with end stage renal failure was performed to assess the clinical benefits resulting from correction of anaemia. Ten of the 11 children completed 36 weeks of the study and seven completed both 24 week limbs. Subcutaneous administration of r-HuEpo twice a week resulted in an increase in haemoglobin concentration, from 73 to 112 g/l. This was associated with an objective improvement in exercise tolerance, and a subjective improvement in physical performance and health, and better school attendance. No consistent effect was seen on appetite, growth, psychosocial functioning, biochemical control, or peritoneal dialysis efficiency. A small but clinically unimportant increase in systolic and diastolic blood pressure was seen in five children. One child on antihypertensive treatment required an increase in dosage during r-HuEpo while another child required a reduction in treatment. These findings, together with the important cardiac benefits previously described during r-HuEpo treatment, support the use of r-HuEpo in all children with end stage renal failure and anaemia.

Cardiac abnormalities in end stage renal failure and anaemia.

Thirteen anaemic children on dialysis were assessed to determine the incidence of cardiac changes in end stage renal failure. Nine children had an increased cardiothoracic ratio on radiography. The electrocardiogram was abnormal in every case but no child had left ventricular hypertrophy as assessed by voltage criteria. However, left ventricular hypertrophy, often gross, was found on echocardiography in 12 children and affected the interventricular septum disproportionately. Cardiac index was increased in 10 patients as a result of an increased left ventricular stroke volume rather than heart rate. Left ventricular hypertrophy was significantly greater in those on treatment for hypertension and in those with the highest cardiac index. Abnormal diastolic ventricular function was found in 6/11 children. Children with end stage renal failure have significant cardiac abnormalities that are likely to contribute to the high cardiovascular mortality in this group. Anaemia and hypertension, or its treatment, probably contribute to these changes. Voltage criteria on electrocardiogram are of no value in detecting left ventricular hypertrophy. Echocardiography must be performed, with the results corrected for age and surface area, in order to detect and follow these abnormalities.

Short term correction of anaemia with recombinant human erythropoietin and reduction of cardiac output in end stage renal failure.

Children with end stage renal failure and anaemia have an increased cardiac index and often gross ventricular hypertrophy. The contribution of anaemia to these abnormalities is uncertain. Eleven children with end stage renal failure and anaemia (haemoglobin concentration < 90 g/l) were enrolled into a single blind, placebo controlled, crossover study to assess the cardiovascular effects of reversing anaemia using subcutaneous human recombinant erythropoietin (r-HuEpo). Each limb lasted 24 weeks; seven children completed both limbs of the study. Haemoglobin increased with r-HuEpo, remaining above 100 g/l for a mean of 11 weeks. Cardiac index fell as a result of a reduction in both left ventricular stroke volume and heart rate. Left ventricular end diastolic diameter also decreased. In five children left ventricular wall thickness and left ventricular mass decreased with r-HuEpo, but this failed to reach significance for the whole group. Blood pressure did not change in six normotensive children completing an r-HuEpo limb; the decrease in cardiac index was therefore balanced by an increase in peripheral vascular resistance. Three children were taking anti-hypertensive treatment at the start of the study; one required an increase, and one a decrease, in treatment during the r-HuEpo limb. Short term treatment with r-HuEpo reduces cardiac index. A longer study is needed to determine whether this will, in time, result in a significant reduction in left ventricular hypertrophy.

The direct measurement of glomerular filtration rate from the continuous monitoring of DTPA clearance.

A method of measuring glomerular filtration rate is proposed, intended for use during gamma camera renography and involving the continuous monitoring of DTPA activity in blood, a single blood sample, and a urine collection. Data obtained from experiments using a CsI scintillation detector are presented and used to demonstrate the validity of the method. In a comparison with a direct measurement of renal clearance of DTPA the proposed method showed an average overestimate of 13% compared to an overestimate of 30% for an uncorrected single-compartment model calculation of filtration rate. Some limited data using a gamma camera to monitor the DTPA activity in blood are also presented.

Oesophageal and severe gut involvement in the haemolytic uraemic syndrome.

Between 1982 and 1989, 78 children with diarrhoea-associated haemolytic uraemic syndrome (HUS) were referred to this hospital. Most presented with abdominal pain, bloody diarrhoea and vomiting. Seven had severe gastrointestinal involvement, four of whom required resection for bowel perforation or necrosis. One also developed an oesophageal stricture, a previously unreported complication of HUS. These seven children had a high incidence of other complications including hypertension, and cerebral and pancreatic involvement. One died from severe cerebral involvement, one has a residual neurological deficit and one has residual renal impairment. Severe gastrointestinal involvement did not significantly affect the long-term outcome. Simple haematological indices helped predict severe gut involvement. Four of the 78 children had undergone appendicectomy before the diagnosis of HUS was made. The operative findings were in no case typical of primary acute appendicitis, although histological examination did confirm inflammation of the appendix in two patients. Diagnosis is difficult in early disease, but increased awareness may help prevent unnecessary appendicectomy.