1 South African Paediatric Surgical Outcomes Study (SAPSOS) A South African national, multi-centre fourteen day evaluation of patient care and clinical outcomes for paediatric patients undergoing surgery Study protocol version 1 07 July 2016 Signature Alexandra Torborg Principal investigator Signature Larissa Cronje Signature Jennifer Thomas
2 Co-lead investigators Principal investigator contact details Dr Alexandra Torborg Perioperative Research Group, Department of Anaesthetics Nelson R Mandela School of Medicine Private Bag 7, Congella, 4013 Kwazulu-Natal, South Africa E-mail: alexandra@iafrica.com Telephone: +27 (0)833850217 Facsimile: +27 (0) 31 260 4433 Co Lead-Investigators Dr Larissa Cronje Department of Anaesthetics Nelson R Mandela School of Medicine Private Bag 7, Congella, 4013 Kwazulu-Natal, South Africa E-mail: lallipop@mweb.co.za Telephone: +27 (0) 832698866 Facsimile: +27 (0) 31 260 4433 Emeritus Professor Jennifer Thomas Department of Anaesthesia University of Cape Town Division of Paediatric Anaesthesia Red Cross War Memorial Children s Hospital, Cape Town
3 Steering committee Chair 1. Alexandra Torborg MBChB FCA(SA), Department of Anaesthetics, University of KwaZulu-Natal, Durban, South Africa Current Members 1. Larissa Cronje MBChB FCA(SA) Department of Anaesthetics, University of KwaZulu- Natal, Durban, South Africa 2. Jennifer Thomas, BSc, STD (Edu) MBChB FFA University of Cape Town, Cape Town, South Africa Management Committee Head of Anaesthesia Departments of the following universities: University of Cape Town University of the Free State University of KwaZulu-Natal University of Limpopo University of Pretoria University of Stellenbosch Sefako Makgatho Health Sciences University University of the Witwatersrand Walter Sisulu University Private Practice Hospitals
4 Funders None as yet.
5 Table of Contents Introduction, background and rationale for the study 6 Research questions 7 Primary objective 7 Secondary objectives 7 Methods 8 Inclusion criteria 8 Exclusion criteria 8 Centres 8 Ethics approval 9 Data collection and collation 9 Dataset 10 Case record forms 10 Sample size calculation 11 Statistical analysis 11 Primary outcome measure 12 Secondary outcome measures 12 Organisation 12 Provincial centre co-ordinators 12 Local co-ordinators 12 Data management and ownership 13 Publication plan 13 Deliverables 13 Appendices 14 Appendix 1 14 South African Paediatric Surgical Outcomes Study (SAPSOS) Operating Room case record form 14 Appendix 2 15 South African Paediatric Surgical Outcomes Study (SAPSOS) Post-operative case record form 15 Appendix 3 16 South African Paediatric Surgical Outcomes Study (SAPSOS) Critical Care case record form (CC CRF) 16 Appendix 4 17 South African Paediatric Surgical Outcomes Study (SAPSOS) Hospital Information record form 17 References 18
6 Introduction, background and rationale for the study It is conservatively estimated that 11%-15% of the global burden of disease is surgically treatable.(1) This percentage is higher in children and in Low- and Middle-Income Countries (LMIC).(2-4) Studies suggest that by age 15, up to 85% of children have a surgically treatable condition.(5) Surgery and anaesthesia services require greater infrastructure than other public health programmes,(6) but surgery is a cost effective intervention even in poorly resourced settings.(6-8) Significant disparities exist in the access to and safety of surgical and anaesthesia services in LMIC compared to High-Income Countries (HIC).(9) This translates to a large unmet burden of disease and avertable disability and mortality in LMIC.(3, 10, 11), Access Despite 312.9 million operations performed globally in 2012 (12) it is estimated that in LMIC between two and five billion people lack access to surgery.(4, 10) Children, especially those with surgically treatable congenital anomalies, are disproportionately affected.(1, 13, 14) Data from certain Low-income countries (LIC) indicate that only 13,5% of children receive operative procedures required,(15) and only 3,5% of the disease burden for neonatal surgery is met.(16) Safety Compared to HIC, peri-operative and anaesthetic-related mortality for both adult and paediatric populations, shows a two- to three-fold increase in mortality in Middle-income countries (MIC) and may be up to 100- fold greater in LIC.(9, 17, 18) Paucity of data from LMIC may underestimate these figures. Risk factors associated with poor outcomes in paediatric patients are similar across all income countries and include: ASA Status: > III; Age: neonates and age <1 year; and emergency surgery.(17) Contributing Factors Factors contributing to the disparities between HIC and LMIC are well documented and reflect lack of funding and investment in surgical and anaesthesia care by governments or heath care funders.(4, 19) They include: i) Lack of infrastructure (including lack of heath care facilities, poor quality of facilities or difficult access to such facilities); ii) Inadequate human resources and lack of trained surgical, anaesthetic or nursing personnel personnel; iii) Lack of essential equipment and medication (including blood or appropriate fluids); iv) Lack of governance or safety practices and v) Lack of reliable prospective data.(4, 17, 19, 20) Progress The World Health Organisation (WHO) Millennium Development Goals (MDG) focused financial, political and policy resources on non-surgical health priorities especially in LMIC, including South Africa.(6-8, 21) Recognition of the unmet public health burden of surgically treatable disease in these areas has gained momentum and refocused the post-2015 goals.(4) Important programmes include the World Health Organization (WHO) Global Initiative for Emergency and Essential Surgical Care (GIEESC)(7, 22) and the Lancet Commission on Global Surgery.(23, 24). Research Agenda
7 In order to strengthen these programs, it is essential that reliable prospective data are gathered, especially from LMICs.(4) Such data can: i) Provide baseline safety data of the perioperative and anaesthesia services; ii) Delineate system, personnel or patient factors associated with poor outcomes and iii) Identify the gap between current access and unmet need for peri-operative services. Pragmatic trials with simple peri-operative metrics are appropriate in LMIC.(25) South Africa South Africa is a MIC and has a complex dual health care system. Public health care serves the majority of the population yet is disproportionately underfunded compared to private care.(21) The South African Surgical Outcomes Study (SASOS)(26) has given some interesting and helpful insights into the peri-operative milieu in public hospitals in South Africa. SASOS describes an adult population, yet in South Africa, 30% of the population is 15 years old.(27) The South African Perioperative Research Group (SAPORG) recently identified a national prospective observational study of the outcomes associated with paediatric surgical cases as a national research priority. (ref) Study Rationale There are few data of paediatric peri-operative morbidity and mortality in South Africa. There is little information on the burden or profile of surgical disease in the paediatric population, the level of anaesthesia or surgical care (specialist versus non-specialist) for paediatric patients, the quality of peri-operative care or contributing factors to poor outcomes.(28) In order to understand current paediatric peri-operative morbidity and mortality, it is important to start obtaining these data. Risk factors can be identified and changes can be in implemented accordingly to improve future outcomes. This study has important public health implications for South Africa as surgery is now recognized internationally as an essential part of public health, yet still needs to be defined as a priority in South Africa. Policy-makers and healthcare providers need evidence to plan resource allocation in a way that will improve quality and outcomes. The data from SAPSOS and SASOS, would provide a platform for government and health care providers in South Africa to appropriately allocate funding, make policy decisions and plan future peri-operative healthcare in South Africa. Research questions Primary objective 1. To confirm the incidence of in-hospital postoperative complications including mortality and critical care admission in paediatric surgical patients in South Africa Secondary objectives 1. To identify factors associated with in-hospital postoperative complications in paediatric surgical patients in South Africa
8 2. To describe the profile of paediatric surgical procedures performed at different levels of hospitals in South Africa 3. To identify the level of training and experience of perioperative caregivers for paediatric surgical patients in South Africa 4. To identify the current utilization of and risk factors for critical care admission following paediatric surgery in South Africa 5. To describe the proportional contribution of communicable, non-communicable diseases, congenital and traumatic injuries to in-hospital mortality and critical care admissions in paediatric surgical patients in South Africa 6. To identify system factors prevailing in hospitals providing paediatric surgical care such as availability of human resources, equipment, medication and blood Methods Fourteen-day, South African national multi-centre prospective cohort study of paediatric patients (<16 years) undergoing surgery. This study will be registered on ClinicalTrials.gov. The SAPSOS study (as was the SASOS study(26)) will be based on the methodology of the EuSOS study.(29) Inclusion criteria All consecutive patients < 16 years, admitted to participating centres during the study period who undergo elective and non-elective surgery. This will include day case surgery and operative procedures outside operating theatres where a general anaesthetic (GA) is performed. Recruitment will commence during the fourteen-day study cohort period which will run from 07h00 on 22.05.2017 06h59 on 05.06.2017. Exclusion criteria 1. Patients undergoing radiological or other procedures not requiring general anaesthesia, or where general anaesthesia is performed but no procedure is done e.g. GA during a magnetic resonance imaging (MRI). 2. Obstetric surgical procedures. Centres We aim to recruit from as many South African centres as possible. We anticipate that all nine Medical University in South Africa will participate (University of Cape Town, University of the Free State, University of KwaZulu-Natal, University of Limpopo, University of Pretoria, University of Stellenbosch, Sefako Makgatho Health Sciences University, University of the Witwatersrand, and Walter Sisulu University), and all the hospitals they support and serve will participate in this study. We are hopeful that we also include State hospitals which are not supported by the South African universities as well as hospitals in the private sector. Each centre will receive an individual report allowing comparison of their dataset to that of the overall national cohort.
9 Ethics approval Ethics approval will be obtained from each university centre. Steering and management committee members will ensure ethics approval is obtained from their respective centres. Centres will not be permitted to record data unless ethics approval or an equivalent waiver is in place. Section 71(3)(a)(ii) of the National Health Act (NHA) requires the Minister of Health to consent to non-therapeutic health research with minors, after considering whether four criteria are met. The Minister has delegated authority to provide such Ministerial Consent to fully registered research ethics committees (RECs). In additional to other protocol and ethics documentation, researchers must submit a Form A providing details under each criterion. We believe that the SAPSOS study fulfills all four criteria. Criterion 1: The research objectives cannot be achieved except by the participation of minors. Data from adult surgery cannot be extrapolated to pediatric patients. Paediatric patients have unique physiological and anatomical differences compared to adults, the profile of diseases differ, and specialized training and skills are required to manage them. As risk factors for poor perioperative outcomes may differ from adults, it is essential to conduct perioperative research on minors. Criterion 2: The research is likely lead to an improved scientific understanding of certain conditions, diseases or disorders affecting minors. As highlighted in the introduction, 30% of the South African population is under the age of 15. Minors are disproportionately affected by the burden of untreated surgical disease and access to safe surgery is a global priority. The perioperative outcomes and milieu of paediatric surgery is unknown in South Africa. In order to improve outcomes and increase access to surgery for minors, appropriate resources need to be allocated. This study will provide essential information to achieve these goals. Criterion 3: Any consent given to the research is in line with public policy. We expect that in most, if not every participating centre, that there will be no requirement for individual patient consent as all data will be anonymised and is already recorded as part of routine clinical care. This international precedent has already been set, as in the original EuSOS study, where consent was waived in 27 of the 28 European countries participating.(29) In South Africa, children are protected as a vulnerable research population and as such require individual informed consent.(30) However there are international precedents for waiver of consent in children of if the study poses minimal risk to participants, and has significant public health benefit.(30) We will therefore apply for a waiver of individual patient consent, as we do not believe this would not be at odds with public policy. Criterion 4: The research does not pose a significant risk to minors; and if there is some risk, the benefit of the research outweighs the risk. This study is in effect a large scale clinical audit of data already routinely collected, thus does not pose a significant risk to the study population. Data collection and collation Each individual centre will collect and record data on either an electronic or paper case record form (CRF) for every patient recruited. Paper CRFs will be stored within a locked office in each centre as they will include identifiable patient data in order to allow follow-up of clinical
10 outcomes. Data will then be pseudo-anonymised by generation of a unique numeric code and transcribed by local investigators onto a secure, password protected internet based electronic CRF. Each patient will only be identified on the electronic CRF by their numeric code; thus the co-ordinating study team cannot trace data back to an individual patient without contact with the local team. A participant (patient) list will be used in each centre to match identifier codes in the database to individual patients in order to record clinical outcomes and supply any missing data points. Access to the data entry system will be protected by username and password delivered during the registration process for individual local investigators. All electronic data transfer between participating centres and the co-ordinating centre will be encrypted using a secure protocol (HTTPS/SSL 3.0 or better). Where individual centres are unable to access the internet based case record form, pseudoanonymised (coded) facsimile (fax) data transfer will be available to a secure, dedicated fax machine in the co-ordinating office. Pseudo-anonymised (coded) data may also be sent by mail to the coordinating centre if necessary. Each centre will maintain a secure trial file including a protocol, local investigator delegation log, ethics approval documentation, the participant list, and other additional documentation such as trial definitions. A final summary printout of included patients with major variables should be produced for each centre together with final data submission to double check for completeness and accuracy. Dataset A realistic data set will be fundamental to the success of the investigation, and this was confirmed in the EuSOS and SASOS studies where nearly complete data was available on patients. Following advice from the SASOS steering committee, we have therefore adopted this dataset with minor changes applicable to paediatric patients. These key data points will not discourage centres from participating because of an excessive burden of data collection. The reliability of data collection will be analysed formally using K-statistics or intra-class correlation coefficients as appropriate. Centre co-ordinators may request the addition of a limited number of data points to support the national SAPSOS data collection and for subsequent regional analyses. All additional data points must be discussed with the co-principal investigators and if necessary the steering committee. Centre-specific data for each hospital will be collected once including: district/regional/tertiary centre, number of operating rooms, number of surgical, anaesthetic and intensive care unit (ICU) doctors, nurse ratios, number and level of critical care beds, availability of paediatric surgical wards, equipment appropriate to paediatric surgery and anaesthesia, availability of medication and blood, details about the reimbursement status of the hospital and public holidays or other local factors affecting patient throughput during the study period. Case record forms 1. An operating room case record form (CRF) will be completed for every eligible patient who undergoes surgery during the fourteen day cohort period (appendix 1).
11 2. Patients will be followed up until hospital discharge. This will be censored at thirty days i.e. patients will be followed up until discharge or for thirty days whichever is the shorter period. A post-operative CRF will be completed at such time (appendix 2). 3. If a patient is admitted to critical care at any time during the follow-up period, then a critical care CRF will be completed (appendix 3). The critical care CRF may therefore be completed for patients admitted to critical care after the fourteen day cohort period is complete. 4. A centre-specific data form as described above (appendix 4). Sample size calculation We intend to recruit as many patients as possible in a fourteen day period, in order to establish a large, representative sample from all participating South African centres. Based on audit data from potential participating sites, we believe that it is possible that the sample size may be close to 2,500 patients. Perioperative mortality and morbidity is difficult to estimate due to the paucity of paediatric data from MLIC. Assuming an overall complication rate following surgery of 5%, a sample size of 2,500 patients will yield 125 postoperative events. This will allow the inclusion of 10 to 15 variables in a logistic regression model for morbidity (including mortality and critical care admission). Statistical models may need to be adapted to the event rate provided by the sample recruited. Statistical analysis The data to be collected are all collected as part of routine clinical care. Categorical variables will be described as proportions and will be compared using chi-square tests. Continuous variables will be described as mean and standard deviation if normally distributed or median and inter-quartile range (IQR) if not normally distributed. Comparisons of continuous variables between groups will be performed using t-tests, one-way ANOVA or equivalent non parametric tests as appropriate. Univariate analysis will be performed to test factors associated with morbidity including planned and unplanned admission to critical care or in-hospital death. Generalized linear mixed models using a logit link will be used to identify independent risk or prognostic factors for binary outcomes. These will include one-level models and hierarchical two-level models to account for the expected correlation in outcomes within hospitals. Data will first be analysed by Province, and then at the Country level, using Province as an independent variable. A stepwise approach will be used to enter new terms into the regression models. Factors will be entered into the models based on their univariate relation to outcome (p<0.05), biological plausibility and low rate of missing data. Results will be reported as adjusted odds ratios (OR) with 95% confidence intervals. A single final analysis is planned at the end of the study.
12 Primary outcome measure 1. Incidence of in-hospital postoperative complications in paediatric surgical patients in South Africa. Secondary outcome measures 1. Rate of mortality on the day of surgery for patients < 16 years undergoing surgery in South Africa. 2. The in-hospital mortality rate for patients < 16 years undergoing surgery in South Africa. 3. Rate of admission to critical care. Organisation The steering committee will be chaired by AT. The management team will be appointed by the Steering Committee. The duties of this team will include administration of all task projects, communication between project partners (including funders, steering committee members, national and local co-ordinators, data collation and management and preparation of reports for individual study sites. The Steering Committee is responsible for the scientific conduct and consistency of the project. The Steering Committee will ensure communication between the funder(s), study management team and co-ordinators as necessary. Provincial centre co-ordinators Provincial centre co-ordinators will be appointed by the steering committee to lead the project within individual provincial centres and: Identify local co-ordinators in participating hospitals Assist with translation of study paperwork as required Ensure distribution of research manuals, ecrf and other materials Ensure necessary regulatory approvals are in place prior to the start date Ensure good communication with the participating sites in his/her province Local co-ordinators Local co-ordinators in individual institutions will have the following responsibilities: Provide leadership for the study in their institution Ensure all relevant regulatory approvals are in place for their institution Ensure adequate training of all relevant staff prior to data collection Supervise daily data collection and assist with problem solving Act as guarantor for the integrity and quality of data collected Ensure timely completion of ecrfs Communicate with the relevant national coordinator
13 Data management and ownership On behalf of the Steering Committee, the Department of Anaesthetics, University of Kwazulu- Natal will act as custodian of the data. The Steering committee will retain the right to use all pooled data for scientific and other purposes. Members of the SAPSOS study group will have the right to access the pooled data for research purposes provided the research proposal has been reviewed and deemed satisfactory by the Steering Committee. The primary consideration for such decisions will be the quality and validity of any proposed analysis. Only summary data will be presented publicly and all institutions will be anonymised except in the individualised report provided to each institution at the end of the study. Individual patient data provided by participating sites remain the property of the respective institution. Publication plan Data will be presented and disseminated in a timely manner. The steering committee will appoint a writing committee to draft the scientific report(s) of this investigation. Specific funding will be requested to allow publication of data on an open access basis. On request, centres will be provided with an individual report allowing comparison of their individual centre s summary data to that of their national cohort. In line with the principles of data preservation and sharing, the Steering Committee will, after publication of the overall dataset, consider all reasonable requests to make the dataset available in whole or part for secondary analyses and scientific publication. The Steering Committee will consider the scientific validity and the possible effect on the anonymity of participating centres prior to granting any such requests. Where appropriate, a prior written agreement will set out the terms of such collaborations. The Steering Committee will consider proposals for secondary analyses on the basis of the scientific quality of the proposal. The Steering Committee will not consider repeat analyses on smaller geographical subsets, but would consider subgroup analysis of specific case mixes. The Steering Committee must approve the final version of all manuscripts prior to submission, whether they relate to part or all of the SAPSOS dataset. Deliverables The main deliverables will be scientific reports of preliminary findings for general and specialty journals, abstracts for presentation to national and international meetings including those of the supporting societies and a final report summarising the overall findings.
14 Appendices Appendix 1 South African Paediatric Surgical Outcomes Study (SAPSOS) Operating Room case record form
15 Appendix 2 South African Paediatric Surgical Outcomes Study (SAPSOS) Post-operative case record form
16 Appendix 3 South African Paediatric Surgical Outcomes Study (SAPSOS) Critical Care case record form (CC CRF)
17 Appendix 4 South African Paediatric Surgical Outcomes Study (SAPSOS) Hospital Information record form
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