Major technological advances in paediatric surgical and intensive care in recent decades, particularly for neonates, have resulted in the survival of children with previously life-threatening CHD;Reference Knowles, Bull, Wren and Dezateux 1 yet, CHDs remain the most common cause of infant death in the United Kingdom.Reference Kurinczuk, Hollowell and Boyd 2 , Reference Billett, Majeed, Gatzoulis and Cowie 3 Although many deaths are associated with surgery, national cardiac audit data suggest that significant numbers of deaths occur more than 30 days after neonatal cardiac surgery but within the first postoperative year. 4 Moreover, analysis of 1018 neonates undergoing cardiac surgery in two London hospitals from 2000 to 2009 found that of 176 deaths during the 1st year of life, 116 (66%) occurred during the initial post-surgical hospital stay and 37 (21%) were unexpected late deaths in infants who had been discharged home after apparently successful cardiac surgery. 5 Thus, infants with cardiac disease remain vulnerable even after surgery, particularly if the cardiac intervention involves a series of staged procedures within the first few months of life.Reference Azakie, Merklinger and McCrindle 6 Nevertheless, it is well-recognised that babies with CHDs who survive past their first birthday are subsequently at lower mortality risk during childhood.Reference Billett, Majeed, Gatzoulis and Cowie 3 , Reference Gilboa, Salemi and Nembhard 7 Although considerable emphasis has been placed on quantifying and exploring the risk factors for early postoperative and in-hospital mortality,Reference Jenkins, Gauvreau and Newburger 8 – Reference O’Brien, Clarke and Jacobs 11 far less attention has been paid to later adverse outcomes, particularly those occurring after discharge home, such as deaths in the community or emergency re-admissions.
Guidance on hospital discharge for high-risk neonates from the American Academy of Pediatrics is informed by a robust evidence base describing the specific needs of vulnerable newborns at the time of hospital discharge. 12 Although neonates with complex congenital anomalies are highlighted as a vulnerable population, specific guidance for the post-discharge care of neonates with CHDs is not provided.
Developing effective interventions to address late adverse outcomes through integrated networks of care, involving specialist hospitals and community provision, is a great challenge for health services, but would be timely in the light of the new review of congenital heart services, led by NHS England, 13 which aims to improve standards across the whole patient care pathway. Nevertheless, to achieve optimal outcomes post-discharge in these babies and offer targeted support to vulnerable infants and their families at home in the community, it is also important to understand the risk factors for these late outcomes. We, therefore, undertook a systematic review of the published literature on infants with CHDs to identify the key risk factors, identifiable at the time of discharge home after apparently successful cardiac surgery, which are associated with unexpected death in the community or unplanned re-admission to the hospital.
Methods
In order to ensure a comprehensive review of the evidence and to capture any pertinent risk factors that may not yet have been identified in studies with CHD patients, we used a broad search strategy that included other life-threatening congenital malformations requiring major surgery in the 1st year of life – for example, gastroschisis or diaphragmatic hernia. We used key terms relating to children, congenital abnormalities, surgical procedures, hospital discharge, and adverse outcomes to electronically search MEDLINE (1980 to 1February, 2013), EMBASE (1980 to 1 February, 2013), CINAHL (1981 to 1 February, 2013), Cochrane Library, Web of Knowledge (1980 to 1 February, 2013), and PsycINFO (1980 to 1 February, 2013). Conference abstracts from the Association for European Paediatric Cardiology, the American Heart Association, and the European Surveillance of Congenital Anomalies symposia were searched for the period 2008–2012. A forward citation search was carried out on the reference lists of all the selected studies to identify additional published studies for review.
Studies were eligible for inclusion only if they separately reported outcomes for children discharged from hospital and in-hospital surgical mortality. To ensure relevance to infant survival, only studies involving children up to the age of 5 years were included in the review, and major surgery was defined as requiring intensive or high-dependency care in the postoperative period. Inclusion criteria for the studies included in the review are summarised in Table 1. Titles and abstracts for all studies were independently reviewed by two reviewers, J.T. and J.W., and then full-text papers of the selected studies were assessed by three reviewers, J.T., K.B., and R.K., to determine whether they met the inclusion criteria. Any discrepancies between the reviewers were resolved through discussion with a fourth reviewer – J.W.
Summary of the eligibility criteria for inclusion in the review.
Data extraction was independently completed by two reviewers, J.T.and R.K., using a standard proforma that included information on study design, population, diagnosis, comparison groups, outcomes, and risk factors. Studies were assessed for methodological quality of study design using levels of evidence rated from “one” for most rigorous trials – for example, randomised controlled trial – to “four” for least rigorous trials – for example, retrospective uncontrolled case series.Reference Morley 14 Within each evidence level, studies were assessed as “A” for high quality to “C” for the lowest quality, using predetermined criteria such as confounding, completeness of follow-up, and objective measurement of outcomes.
The outcomes of interest were unexpected death or unplanned re-admission to the hospital in the 1st year of life after discharge following cardiac surgery. Factors associated with increased mortality or re-admission risk are presented in a narrative synthesis.
The protocol and search strategy are registered (PROSPERO; CRD42013003483).Reference Tregay, Wray, Brown and Knowles 15
Results
Study selection
There were 17 studies identified through systematic searches and further six studies through forward citations. Of 23 full-text papers reviewed, eight studies failed to meet the inclusion criteria, resulting in 15 studies eligible for review (Fig 1). Despite our inclusive search strategy, no studies of post-surgical outcomes for children with non-cardiac congenital anomalies met the inclusion criteria.
PRISMA flowchart showing study selection process.
The review included eight retrospective reviews of surgical cases,Reference Ashburn, McCrindle and Tchervenkov 16 – Reference Simsic, Bradley, Stroud and Atz 23 four retrospective cohort studies,Reference Chang, Rodriguez, Lee and Klitzner 24 – Reference Kogon, Jain and Oster 27 two case–control studies,Reference Hehir, Dominguez and Ballweg 28 , Reference Mackie, Gauvreau and Newburger 29 and one randomised controlled trial that was reported in two papers.Reference Ghanayem, Allen and Tabbutt 19 , Reference Ohye, Schonbeck and Eghtesady 30 Only three studiesReference Pinto, Lasa and Dominguez 22 , Reference Mackie, Gauvreau and Newburger 29 , Reference Ohye, Schonbeck and Eghtesady 30 included a prospective element. Although study designs differed, all studies were rated as good quality (Table 2). Studies assigned a lower rating failed to address some potential confounding factors. In total, 10 reports were of patients with functional single ventricle diagnosis,Reference Ashburn, McCrindle and Tchervenkov 16 , Reference Carlo, Carberry and Heinle 17 , Reference Ghanayem, Allen and Tabbutt 19 – Reference Mahle, Spray, Gaynor and Clark 21 , Reference Simsic, Bradley, Stroud and Atz 23 , Reference Hebson, Oster and Kirshbom 26 , Reference Hehir, Dominguez and Ballweg 28 – Reference Ohye, Schonbeck and Eghtesady 30 which was most often hypoplastic left heart syndrome. A total of 14 papers involved patients who underwent cardiac surgery during the 1st year of life, and the remaining studyReference Chang, Rodriguez, Lee and Klitzner 24 included cardiac patients operated up to the age of 18 years with results provided separately for each age group. Only two studies were not conducted in the United States.Reference Ashburn, McCrindle and Tchervenkov 16 , Reference Hansen, Uebing and Furck 20 In total, 29,019 patients were followed-up for mortality outcomes, of whom 1113 (4%) died; 452 (12%) of 3672 children died after single ventricle surgery compared with 661 (3%) of 25,347 children who underwent other types of cardiac surgery. Of 1639 children who were observed in three studies of unplanned re-admission, 173 (11%) were re-admitted to the hospital during the study follow-up period. Table 3 summarises the included papers.
Summary of study quality by levels of evidence.
LOE=levels of evidence; RCT=randomised controlled trial
Rated A (high quality) to C (low quality)
Studies meeting criteria for review (n=15) examining risk factors for post-discharge mortality and/or unplanned hospital re-admission.
ECMO=extracorporeal membrane oxygenation; HLHS=hypoplastic left heart syndrome; MBTS=Modified Blalock–Taussig Shunt; RACHS=Risk Adjustment in Congenital Heart Surgery; RVPAS=right ventricle to pulmonary artery shunt
Adverse outcomes
Reported mortality varied markedly and was influenced by the study population at risk as well as the duration of follow-up. A total of five studiesReference Ashburn, McCrindle and Tchervenkov 16 , Reference Ghanayem, Allen and Tabbutt 19 , Reference Simsic, Bradley, Stroud and Atz 23 , Reference Hebson, Oster and Kirshbom 26 , Reference Hehir, Dominguez and Ballweg 28 involved children with single ventricle diagnoses undergoing staged palliative surgery and reported “inter-stage” mortality between first and second stage surgery that ranged from 8 to 16%, with follow-up ending at around 1 year after surgery in most studies. In addition, two studies focussed on “unexpected” inter-stage deaths, defined as acute events or sudden cardiovascular collapse, and reported 4–5% unexpected deaths in neonates discharged home between stages 1 and 2.Reference Mahle, Spray, Gaynor and Clark 21 , Reference Ohye, Schonbeck and Eghtesady 30 Carlo et alReference Carlo, Carberry and Heinle 17 and Hansen et alReference Hansen, Uebing and Furck 20 reported inter-stage mortality of 9% for children discharged home between second – superior cavopulmonary anastomosis or bi-directional Glenn surgery – and third stage – Fontan surgery. Two studies investigated post-discharge mortality after all types of cardiac surgery: Chang et alReference Chang, Rodriguez, Lee and Klitzner 24 reported a low mortality of 0.62% at 1 year after any cardiac surgery undertaken in children up to 18 years of age,Reference Chang, Rodriguez, Lee and Klitzner 24 whereas Pinto et alReference Pinto, Lasa and Dominguez 22 found a higher mortality of 8% in the 2 years following discharge after neonatal congenital heart surgery. Mortality over 10% was reported in studies focussing on specific higher-risk cardiac defect subgroupsReference Fixler, Nembhard and Xu 25 or patients discharged home on mechanical ventilation.Reference Edwards, Kun and Keens 18
In total, two studies evaluated unplanned hospital re-admissions distinct from mortality,Reference Pinto, Lasa and Dominguez 22 , Reference Kogon, Jain and Oster 27 and one further studyReference Mackie, Gauvreau and Newburger 29 reported unplanned re-admissions as part of a combined outcome measure of mortality and re-admission. Re-admission rates within 30 days of hospital discharge ranged from 10Reference Kogon, Jain and Oster 27 to 30%Reference Mackie, Gauvreau and Newburger 29 and at 2 years post-discharge were 45%.Reference Pinto, Lasa and Dominguez 22 Variations were influenced by duration of follow-up and differences in data collection methods that included hospital records reviewReference Kogon, Jain and Oster 27 , Reference Mackie, Gauvreau and Newburger 29 and telephone survey.Reference Pinto, Lasa and Dominguez 22
Risk factors associated with adverse outcomes
Although many different factors were investigated (Table 4), the findings relating to individual factors were inconsistent; this may reflect the heterogeneity of participant characteristics and study designs. Table 4 summarises the factors investigated by different studies and indicates whether these were found to increase mortality risk.
Summary of factors examined in the 15 studies.
AV=atrioventricular; HLHS=hypoplastic left heart syndrome.
* Cardiac surgical procedures defined in these studies were as follows: palliative procedures, Norwood stage 1, bi-directional Glenn, shunt construction, thoracic vessel procedures, truncus arteriosus repair, total anomalous pulmonary venous return (TAPVR) repair, open valvotomy
Individual and family factors
Ethnicity,Reference Ghanayem, Allen and Tabbutt 19 , Reference Pinto, Lasa and Dominguez 22 , Reference Fixler, Nembhard and Xu 25 , Reference Kogon, Jain and Oster 27 socio-economic status,Reference Ghanayem, Allen and Tabbutt 19 , Reference Fixler, Nembhard and Xu 25 , Reference Mackie, Gauvreau and Newburger 29 and non-cardiac malformations or genetic syndromesReference Fixler, Nembhard and Xu 25 , Reference Kogon, Jain and Oster 27 , Reference Mackie, Gauvreau and Newburger 29 were the most frequently evaluated individual factors. Socio-economic deprivation, assessed through measures such as household income,Reference Mackie, Gauvreau and Newburger 29 family income below the national poverty threshold,Reference Ghanayem, Allen and Tabbutt 19 and deprivation index of the residential area,Reference Fixler, Nembhard and Xu 25 and Hispanic ethnicityReference Morley 14 , Reference Ghanayem, Allen and Tabbutt 19 , Reference Pinto, Lasa and Dominguez 22 were highlighted as risk factors for mortality and unplanned hospital re-admission in US studies. Preterm birthReference Ghanayem, Allen and Tabbutt 19 , Reference Fixler, Nembhard and Xu 25 and low birth weightReference Ashburn, McCrindle and Tchervenkov 16 , Reference Fixler, Nembhard and Xu 25 were risk factors for mortality, but patient gender was not significantly associated with adverse outcomes.Reference Carlo, Carberry and Heinle 17 , Reference Chang, Rodriguez, Lee and Klitzner 24 , Reference Fixler, Nembhard and Xu 25 , Reference Hehir, Dominguez and Ballweg 28 Children living 90–300 minutes from the cardiac centre were at significantly lower risk of unplanned re-admissionReference Pinto, Lasa and Dominguez 22 compared with families living under 90 minutes away, but there was no association with mortality.Reference Pinto, Lasa and Dominguez 22 , Reference Fixler, Nembhard and Xu 25 Family factors including maternal education, marital status, and country of birth were not associated with adverse outcomes.Reference Fixler, Nembhard and Xu 25
Cardiac diagnosis and procedural factors
Infants with more complex hypoplastic left heart variantsReference Ashburn, McCrindle and Tchervenkov 16 , Reference Carlo, Carberry and Heinle 17 , Reference Ghanayem, Allen and Tabbutt 19 , Reference Hansen, Uebing and Furck 20 , Reference Hehir, Dominguez and Ballweg 28 were at higher risk of mortality or re-admission. Children undergoing more complex operations, based on the Risk Adjustment in Congenital Heart Surgery 1 system,Reference Jenkins, Gauvreau and Newburger 8 , Reference Jenkins 31 were at greater risk.Reference Edwards, Kun and Keens 18 , Reference Pinto, Lasa and Dominguez 22 , Reference Kogon, Jain and Oster 27 Several studies reported that Norwood procedures,Reference Chang, Rodriguez, Lee and Klitzner 24 specific shunt operations,Reference Ashburn, McCrindle and Tchervenkov 16 , Reference Ghanayem, Allen and Tabbutt 19 , Reference Chang, Rodriguez, Lee and Klitzner 24 , Reference Ohye, Schonbeck and Eghtesady 30 total anomalous pulmonary venous connection repair,Reference Chang, Rodriguez, Lee and Klitzner 24 and truncus arteriosus repairReference Chang, Rodriguez, Lee and Klitzner 24 were associated with significantly higher mortality, whereas palliative operationsReference Kogon, Jain and Oster 27 increased the risk of unplanned re-admission. There was insufficient evidence to suggest that intra-operative characteristics such as cardiopulmonary bypass or circulatory arrest time had a negative impact on outcome.Reference Ashburn, McCrindle and Tchervenkov 16 , Reference Simsic, Bradley, Stroud and Atz 23 , Reference Hehir, Dominguez and Ballweg 28
In children undergoing staged palliative operations, older age at first procedure was associated with higher mortality risk,Reference Ashburn, McCrindle and Tchervenkov 16 , Reference Hehir, Dominguez and Ballweg 28 whereas younger age, under 4 months, at the second stage Glenn procedure increased the risk of postoperative complications.Reference Hansen, Uebing and Furck 20 Futhermore, two papersReference Ghanayem, Allen and Tabbutt 19 , Reference Ohye, Schonbeck and Eghtesady 30 reporting findings from the Single Ventricle Reconstruction trial, in which patients with hypoplastic left heart syndrome were randomised to receive different surgical interventions, higher mortality after hospital discharge was observed within the group receiving a modified Blalock–Taussig shunt compared with a right ventricle-to-pulmonary artery conduit; this difference was no longer significant after adjustment for severity of postoperative atrioventricular valvar regurgitation.
Postoperative symptoms/complications
A total of five studies explored postoperative feeding difficulties;Reference Mahle, Spray, Gaynor and Clark 21 , Reference Hebson, Oster and Kirshbom 26 – Reference Mackie, Gauvreau and Newburger 29 three of these identified feeding difficulties, including the need for gastrostomy tube placement,Reference Hebson, Oster and Kirshbom 26 as a risk factor for mortality or unplanned re-admission. Peri- and postoperative arrhythmias were also a significant risk factor for mortality in two studies,Reference Mahle, Spray, Gaynor and Clark 21 , Reference Simsic, Bradley, Stroud and Atz 23 whereas airway complications, prolonged postoperative hospital length of stay, postoperative complications, and medications at discharge were not found to influence outcomes post-discharge.
Discussion
We identified 15 studies that evaluated the potential risk factors associated with mortality or unplanned hospital re-admission in children successfully discharged from the hospital after cardiac surgery for serious CHDs. Factors identified most frequently by these studies as predicting significantly increased risk of adverse events were non-Caucasian ethnicity,Reference Ghanayem, Allen and Tabbutt 19 , Reference Pinto, Lasa and Dominguez 22 , Reference Fixler, Nembhard and Xu 25 , Reference Kogon, Jain and Oster 27 lower socio-economic status,Reference Ghanayem, Allen and Tabbutt 19 , Reference Fixler, Nembhard and Xu 25 , Reference Mackie, Gauvreau and Newburger 29 co-morbid conditions including non-cardiac malformations and syndromes,Reference Fixler, Nembhard and Xu 25 , Reference Kogon, Jain and Oster 27 , Reference Mackie, Gauvreau and Newburger 29 age at surgery,Reference Ashburn, McCrindle and Tchervenkov 16 , Reference Chang, Rodriguez, Lee and Klitzner 24 , Reference Kogon, Jain and Oster 27 , Reference Hehir, Dominguez and Ballweg 28 operative complexity or procedure type,Reference Ashburn, McCrindle and Tchervenkov 16 , Reference Edwards, Kun and Keens 18 , Reference Ghanayem, Allen and Tabbutt 19 , Reference Pinto, Lasa and Dominguez 22 , Reference Chang, Rodriguez, Lee and Klitzner 24 , Reference Kogon, Jain and Oster 27 , Reference Ohye, Schonbeck and Eghtesady 30 and postoperative feeding difficulties.Reference Hebson, Oster and Kirshbom 26 , Reference Kogon, Jain and Oster 27 , Reference Mackie, Gauvreau and Newburger 29 Patient sex, parental factors, intra-operative factors, and postoperative complications were also investigated, but were not found to be independent predictors of post-discharge outcomes.
Our review confirms the significant lack of research into adverse outcomes after hospital discharge following surgery, and highlights the fact that the evidence base to inform post-discharge clinical care and identify infants at high risk for focussed support is extremely limited. As many reports derive from North American studies, and the research population is often limited to infants who have severe and complex cardiac diagnoses requiring staged surgery, care must be taken in generalising the findings from these existing studies to the wider UK population of infants with CHDs.
Despite our broad search strategy that was intended to capture research into other life-threatening anomalies that require surgery during infancy, such as gastroschisis and diaphragmatic hernia,Reference Davis, Firmin and Manktelow 32 the only studies of post-discharge outcomes that met the inclusion criteria concerned CHDs. CHDs, however, have the highest rate of infant deaths of all congenital anomaly subgroups, and this may account for the greater interest in monitoring outcomes after hospital discharge; however, it is also notable that post-discharge outcomes of infants with CHDs came to prominence with the introduction of staged palliative surgery for HLHS, which led to improved early in-hospital outcomesReference Tweddell, Hoffman and Mussatto 33 , Reference McGuirk, Griselli and Stumper 34 and highlighted later inter-stage mortality as an important concern.Reference Ghanayem, Allen and Tabbutt 19 , Reference Ghanayem, Hoffman and Mussatto 35
In three US studiesReference Ghanayem, Allen and Tabbutt 19 , Reference Fixler, Nembhard and Xu 25 , Reference Kogon, Jain and Oster 27 within our review, patients of Hispanic ethnicity were found to be at risk of adverse outcomes relative to Caucasian patients post-hospital discharge. This confirms previous research, which has shown that US Hispanic communities are more likely to experience multiple barriers to healthcare, including language and immigration status, and financial barriers such as lack of health insurance or low family incomes.Reference Cristancho, Garces, Peters and Mueller 36 , Reference Valdez, Giachello and Rodriguez-Trias 37 On the other hand, the impact of ethnicity and socio-economic deprivation demonstrated in US studies may be influenced by an individual family’s ability to pay for care,Reference Cristancho, Garces, Peters and Mueller 36 – Reference Connor, Kline and Mott 43 and the relevance of these findings for the UK healthcare system is uncertain. Nevertheless, there is evidence that lower income families in the United Kingdom also experience a considerable financial burden when caring for their child with CHD and that this may affect care-seeking behaviours.Reference Connor, Kline and Mott 43 The results of our review, therefore, add to the growing body of evidence suggesting that patients from minority ethnic and lower socio-economic groups are more likely to experience barriers to timely and appropriate access to care, and underlines the relevance of these factors to the population of infants with CHDs following hospital discharge.
Postoperative feeding and growth were also significantly associated with adverse outcome in several studiesReference Hebson, Oster and Kirshbom 26 , Reference Kogon, Jain and Oster 27 , Reference Mackie, Gauvreau and Newburger 29 identified within the review, consistent with previous research;Reference Golbus, Wojcik, Charpie and Hirsch 44 however, the relationship between feeding difficulties and adverse outcomes post-discharge is likely to be complex, due to potential confounding with poorer cardiac status and other co-morbidities, and therefore requires further investigation.
A limitation of our review was the rigour of our eligibility criteria, which excluded any studies that did not clearly differentiate between deaths that occurred before and after hospital discharge, and thus may have removed from the review some studies that evaluated additional risk factors to those reported here. Nevertheless, the relative lack of studies reporting post-discharge surgical outcomes may also simply reflect the limited monitoring of late adverse events and specifically of events occurring in the community or primary-care setting.Reference Chang, Rodriguez, Lee and Klitzner 24
Re-admission to hospital will depend both on the child’s clinical state and the response to this by parents and medical staff. It is possible that re-admission signified a timely response to a child’s deteriorating clinical state in some cases, whereas in others it was a response to a child who became seriously unwell. In our review, we considered an unplanned re-admission to be an adverse event, indicating that a child’s condition deteriorated unexpectedly at home, and thus did not experience a stable clinical course after discharge. Nevertheless, it is possible that the risk factors for re-admission may differ from those for deaths, and this may have contributed to the breadth of different risk factors identified.
We identified several key medical and social factors associated with a higher risk of mortality or unplanned hospital re-admission for children discharged from hospital after paediatric cardiac surgery. Some of these risk factors such as feeding difficulties would be amenable to modification through specific interventions, whereas others enable health professionals to identify children who are at greatest risk for adverse outcomes and to offer additional support, such as home monitoring programmes, targeted more effectively at vulnerable children and their families within the community setting. Although there were no studies of social and financial factors within the UK healthcare context, unequal access to care may disproportionately affect minority ethnic communities and low income families and should be a focus for future research in the United Kingdom. Crucially, this review highlights an evidence gap and important need for longer-term studies to investigate the risk factors for out-of-hospital outcomes after surgery separately from in-hospital outcomes. Such evidence would better inform post-discharge care and community-based interventions to improve long-term survival and the quality of life of infants with CHDs.
Acknowledgements
The authors are grateful to the librarians at the UCL Institute of Child Health, London, United Kingdom for their assistance with development of the search strategy for this review.
Financial Support
This project was funded by the National Institute for Health Research Health Services and Delivery Research programme (Project No: 10/2002/29). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR HS&DR programme or the Department of Health. Dr Franklin and Dr Daubeney’s research is supported by the Biomedical Research Unit at the Royal Brompton Hospital.
Conflicts of Interest
None.
Ethical Standards
Not applicable (no human subjects).
