부산대학교 도서관

Background: Congenital anomalies have risen to become the 5th leading cause of death in under 5 year olds globally and 11th leading cause of years of life lost for the global population. This equates to over half a million annual deaths, 97% of which occur in low and middle-income countries (LMICs). Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in LMICs. This PhD aimed to 1) define the mortality from gastrointestinal congenital anomalies in low-, middle- and high-income countries (LICs, MICs and HICs) globally, and 2) develop and implement an interventional care bundle to reduce mortality from gastroschisis in LMICs, a common gastrointestinal congenital anomaly known to have a high neonatal mortality in sub-Saharan Africa (76%) compared to HICs (2%). Methods: I established the Global PaedSurg Research Collaboration consisting of children's surgical care providers across the globe. I designed and led our multicentre, international, prospective cohort study comparing mortality from the seven commonest gastrointestinal congenital anomalies in low-, middle-, and high-income countries globally (Chapter 4). The primary outcome was all-cause, in-hospital mortality. Chi-squared analysis was used to compare mortality between income strata for all study patients, and for each condition separately. Multivariable penalised Lasso regression analysis was used to identify factors associated with mortality. I designed and undertook a 2-year pre-post Gastroschisis Interventional Study, with study team members at seven tertiary paediatric surgery centres in Ghana, Zambia, Malawi, and Tanzania (Chapter 5). A systematic review, qualitative study and consensus process were used to develop the evidence-based care bundle (Chapters 6, 7 and 8, respectively). This consisted of core components, that were implemented in all seven study centres, and adaptable components unique to each centre to optimise the care bundle for each setting. Patients with simple gastroschisis (intact bowel that can be reduced at the cotside; without necrosis, perforation, atresia, or defect closure necessitating surgery) received the intervention. The primary clinical outcome was all-cause, in-hospital mortality; a difference in the pre- and post-intervention mortality was calculated using Chi-squared analysis. An interim analysis was undertaken where univariable analysis was used to identify factors associated with mortality. These preliminary findings are presented in this thesis (Chapter 9). Results: The Global PaedSurg cohort study included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in HICs, 166 in MICs, and nine in LICs) in 74 countries. Mortality among all patients was 37 (39·8%) of 93 in LICs, 583 (20·4%) of 2860 in MICs, and 50 (5·6%) of 896 in HICs (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in LICs, 97 [31·9%] of 304 in MICs, and two [1·4%] of 139 in HICs; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status, sepsis at presentation, higher American Society of Anesthesiologists score at primary intervention, surgical safety checklist not used, and unavailability of ventilation or parenteral nutrition when needed. Administration of parenteral nutrition and use of a peripherally inserted central catheter or percutaneous central line were associated with lower mortality. For the Gastroschisis Interventional Study, an evidence-based care bundle was established through a systematic review, qualitative study and consensus process, consisting of district hospital and tertiary level interventions. Core components consisted of outreach education on initial resuscitation and early transfer from referring hospitals, with the development of referral networks, and early resuscitation, preformed silo application, bowel reduction, and sutureless closure at the cotside without general anaesthesia, and an accelerated breastfeeding protocol, at the tertiary hospitals. Adaptable components included the use of locally sourced intravenous nutrition and type of intravenous access. In total, over 2000 multi-disciplinary team members were trained at the seven study centres, and their referring hospitals, and all centres successfully established the care bundles into routine clinical practice. Overall gastroschisis mortality was 97% (108/111) at baseline (during the 2-years prior to the study). Mortality from simple gastroschisis fell from 80% (47/59) during the pre-intervention phase to 65% (87/133) during the post-intervention phase (p=0.047). Of all patients with gastroschisis (simple and complex), 3/111 patients survived at the 7 study centres in the 2 years prior to the study and 68/281 survived during the 2-year study period. Hence, the number of patients presenting for care increased during the study as well as the survival. Due to the nature of the condition, it can be assumed that patients who do not present cannot survive. The interim analysis highlighted improvements in care delivery at the district and tertiary levels. The leading cause of death was sepsis. Lower mortality was significantly (p < 0.05) associated with: not having associated anomalies, arriving at the study centre sooner, having a lower ASA score at primary intervention, having a surgeon present at primary intervention, receiving twice daily silo bowel reductions, receiving a sutureless closure, and having a surgeon, neonatologist or paediatrician, and nurse present at defect closure. Conclusion: The Global PaedSurg study highlighted that Sustainable Development Goal 3.2, to end preventable deaths in neonates and children under-5 by 2030, will not be achievable without urgent action to improve neonatal surgical care in LMICs. Interventions to improve survival should focus on 1) improved antenatal diagnosis and delivery at a paediatric surgery centre, 2) early resuscitation and transfer for those born at the district level, and 3) early resuscitation and improved perioperative care, with availability of central venous access, parenteral nutrition and ventilation for neonates, at paediatric surgery centres. The Gastroschisis Interventional Study demonstrates how an evidence-based interventional care bundle can be developed and implemented across multiple LMIC hospitals & countries to improve survival from gastroschisis within the existing healthcare systems; a model that could be used and developed further for a broader range of congenital anomalies.