African Surgical OutcomeS-2 (ASOS-2) Trial
Phase: NA
Conditions: Surgery, Morality
Sponsor: University of Cape Town

 
 
 
 
 
 
African Surgical OutcomeS-2 (ASOS-2) Trial 
 
 
A cluster randomised trial to determine whether increased postoperative 
surveillance of adult African surgical patients reduces postoperative mortality 
 
 
Trial protocol version 7 
19 March 2020 
 
 
 
 
 
 
 
Bruce Biccard  
 
 
 
 
 
Chief investigator 
 
 

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ASOS-2 Trial protocol v.7 
Steering committee 
1. Bruce Biccard MBChB FCA(SA) FFARC(I) MMedSci PhD, Professor and Second 
Chair, Department of Anaesthesia and Perioperative Medicine, Groote Schuur 
Hospital and University of Cape Town, South Africa 
2. Hyla Kluyts MMed (Anaes), Department of Anaesthesiology, Sefako Makgatho 
Health Sciences University, South Africa 
3. Maia Lesosky PhD, Associate Professor, Division of Epidemiology and 
Biostatistics, School of Public Health and Family Medicine, University of Cape 
Town, South Africa 
4. Landon Myer MBChB PhD, Professor and Head of School of Public Health and 
Family Medicine, University of Cape Town, South Africa 
5. Leon du Toit, MBChB FCA (SA), Department of Anaesthesia and Perioperative 
Medicine, Groote Schuur Hospital and University of Cape Town, South Africa 
6. Patrice Forget MD, PhD, Professor, Clinical Chair in Anaesthesia, Institute of 
Applied Health Sciences, School of Medicine, Medical Sciences and Nutrition, 
University of Aberdeen, United Kingdom. Honorary Consultant, NHS Grampian, 
Aberdeen, United Kingdom 
7. Tim Stephens BA (Hons), MSc Global Health and Development, Critical Care and 
Peri-operative Medicine Research Group WHRI, Queen Mary University of London, 
E1 1BB, United Kingdom 
8. RM Pearse MD(Res), Professor of Intensive Care Medicine, Queen Mary 
University of London, Royal London Hospital, London, E1 1BB, United Kingdom 
 
 
 
 
 
 
 
 
 
 

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ASOS-2 Trial protocol v.7 
Chief Investigator contact details 
Professor Bruce Biccard 
Department of Anaesthesia and Perioperative Medicine 
Groote Schuur Hospital and University of Cape Town 
South Africa 
E-mail: bruce.biccard@uct.ac.za 
Mobile: +27 (0) 76 160 6387 
Telephone: +27 (0) 21 406 6143 
Facsimile: +27 (0) 21 406 6589 
 
Funders 
The ASOS-2 Trial is partially supported by a grant (OPP#1161108) from the Bill & 
Melinda Gates Foundation. 
NIHR Research Professorship held by Rupert Pearse 
 
 
 
 
 
 
 
 
 
 
 
 

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ASOS-2 Trial protocol v.7 
Contents 
 
 
1. 
List of abbreviations ........................................................................................................................ 6 
2. 
Summary ......................................................................................................................................... 7 
3. 
Introduction .................................................................................................................................... 8 
4. 
Trial objectives ................................................................................................................................ 9 
4.1 Primary objective .......................................................................................................................... 9 
4.2 Primary outcome measure ........................................................................................................... 9 
4.3 Secondary objective ...................................................................................................................... 9 
4.4 Secondary outcome measure ....................................................................................................... 9 
5. 
Methodology ................................................................................................................................. 10 
5.1 Study design ................................................................................................................................ 10 
5.2 Inclusion criteria .......................................................................................................................... 10 
5.3 Exclusion criteria ......................................................................................................................... 10 
5.4 Study flow diagram ..................................................................................................................... 10 
6. 
Trial procedures ............................................................................................................................ 11 
6.1 Recruitment and screening ......................................................................................................... 11 
6.2 Informed consent and trial participation .................................................................................... 11 
6.3. 
Randomisation ...................................................................................................................... 12 
6.4. 
Trial intervention .................................................................................................................. 12 
Intervention arm ........................................................................................................................... 12 
Control arm ................................................................................................................................... 13 
6.5. 
Data collection and collation ................................................................................................ 13 
Dataset .......................................................................................................................................... 13 
6.6. 
Predefined protocol violation ............................................................................................... 14 
6.7. 
Follow up procedures ........................................................................................................... 14 
6.8. 
Schedule of assessment ........................................................................................................ 14 
7. 
Statistical considerations .............................................................................................................. 15 
7.1. 
Sample size calculation ......................................................................................................... 15 
TABLE 1: Sample size calculations for the ASOS-2 Trial based on a power of 80%, 2-sided α = 
0.05 and a mean cluster size of 100 patients ............................................................................... 15 
7.2. 
Statistical analysis ................................................................................................................. 16 
7.3. 
Subgroup analyses ................................................................... Error! Bookmark not defined. 
7.4. 
Secondary studies ................................................................................................................. 16 
8. 
Research ethics ............................................................................................................................. 18 

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8.1 Ethical principles ......................................................................................................................... 18 
9. 
Data handling and record keeping ................................................................................................ 19 
10. 
Monitoring and auditing ........................................................................................................... 20 
10.1 
Training of investigators ....................................................................................................... 20 
11. 
Trial management and committees .......................................................................................... 21 
11.1 Trial management group........................................................................................................... 21 
11.2 Trial Steering Committee .......................................................................................................... 21 
11.3 Data and Safety Monitoring Board ........................................................................................... 21 
12. 
Data management and ownership ........................................................................................... 22 
13. 
Publication plan and public communication of trial results ..................................................... 23 
References ............................................................................................................................................ 24 
Appendix 1 ............................................................................................................................................ 25 
African Surgical OutcomeS-2 (ASOS-2) Trial: Definitions document ................................................ 25 
Appendix 2 ............................................................................................................................................ 37 
African Surgical OutcomeS-2 (ASOS-2) Trial: Hospital ‘broadcasting’ signage ................................. 37 
Appendix 3 ............................................................................................................................................ 38 
African Surgical OutcomeS-2 (ASOS-2) Trial: Case Record Form (CRF) (Control arm) ...................... 38 
African Surgical OutcomeS-2 (ASOS-2) Trial: Case Record Form (CRF) (Intervention arm) .............. 39 
Appendix 4 ............................................................................................................................................ 40 
ASOS-2 Surgical Risk Calculator Score Card ...................................................................................... 40 
Appendix 5 ............................................................................................................................................ 41 
‘Increased postoperative surveillance’ bedside guide ...................................................................... 41 
 
 
 
 
 

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ASOS-2 Trial protocol v.7 
1. List of abbreviations 
 
ASOS  
 
African Surgical Outcomes Study 
EuSOS  
 
European Surgical Outcomes Study 
ISOS 
 
 
International Surgical Outcomes Study 
 
 
 

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ASOS-2 Trial protocol v.7 
2. Summary 
 
Short title 
ASOS-2 Trial 
Methodology 
An international, multicentre, African cluster randomised trial 
Research 
sites 
Hospitals undertaking adult surgery in participating countries. 
Objectives 
To determine whether increased postoperative surveillance in high-
risk adult surgical patients reduces overall in-hospital mortality in 
surgical patients aged 18 years and over in Africa. 
Number of 
patients 
664 hospital clusters with a recruitment target of 100 patients per 
site (approximately 66,400 patients) 
Inclusion 
criteria 
All consecutive adult patients aged 18 years and over admitted to 
participating centres undergoing elective and non-elective surgery 
Statistical 
analysis 
The primary outcome measure is in-hospital mortality censored at 
30 days of randomisation. The analysis will be conducted according 
to intention-to-treat principles; all participants with a recorded 
outcome will be analysed according to the treatment group to which 
they were randomised.  
Recruitment 
start date 
May 2019 
Recruitment 
end date 
March 2020 
Trial 
duration  
Until hospital discharge, censored at 30 days 
 
 
 

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3. Introduction 
 
The non-cardiac surgical population represents a major global public health burden 
with approximately 234 million major surgical procedures performed worldwide each 
year.1 In unselected non-cardiac surgical patients, reports of early postoperative 
mortality vary between 2 and 4%,2 3 with an annual global mortality of 5 to 10 million. 
Surgery is a cost-effective intervention,4 even in low to middle income countries5 and as 
such it is considered a core component of health.6 The Lancet Commission on Global 
Surgery was established to define safe surgery and develop strategies to ensure the 
adequate provision of safe surgery.7  
 
Recently, the African Surgical Outcomes Study (ASOS) demonstrated, that despite a 
patient low risk profile and low complication rates, patients in Africa were twice as 
likely to die following surgery when compared to the global average.8 ASOS provides the 
most comprehensive data on surgical outcomes in Africa, comprising 25 countries, 247 
hospitals, and data from over 11 000 patients.8 Importantly, 95% of the deaths in ASOS 
occurred in the postoperative period, suggesting that many lives could be saved by 
effective surveillance for physiological deterioration amongst the patients who 
developed complications.8 In ASOS, the median number of combined anaesthesia, 
surgical and obstetric specialists was 0·7 (IQR 0·2-1·9) per 100,000 population,8 which 
is well below the documented inflection point of 20 to 40 specialists per 100,000 
population necessary to significantly decrease surgical mortality.7 
 
It is likely that a major contributor to the high mortality in ASOS was ‘failure to rescue’ 
after a postoperative complication partly due to an inadequacy of sufficient human 
resources necessary to identify postoperative surgical patients at risk. A potential 
solution to improving surgical outcomes in Africa is identification of the high-risk 
surgical patient prior to further physiological deterioration. 
 
The objective of this trial is to assess whether increased postoperative surveillance of 
surgical patients at increased risk of postoperative morbidity or mortality is associated 
with improved survival.  
  
 
 

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4. Trial objectives 
 
4.1 Primary objective  
To determine whether increased postoperative surveillance in high-risk adult surgical 
patients reduces overall in-hospital mortality in adult surgical patients aged 18 years 
and over in Africa. 
 
4.2 Primary outcome measure 
In-hospital mortality, censored at 30 days if the patient is still alive and in-hospital. 
 
4.3 Secondary objective 
To determine whether increased postoperative surveillance in high-risk adult surgical 
patients reduces the overall incidence of the composite of severe in-hospital 
complications and mortality in adult surgical patients aged 18 years and over in Africa. 
 
4.4 Secondary outcome measure 
Composite of severe in-hospital complications and mortality, censored at 30 days if the 
patient is still alive and in-hospital. 
 
A full list of definitions is available in the ‘Definitions document’ in appendix 1. 
 
 
 

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5. Methodology  
 
5.1 Study design 
ASOS-2 is an African, international, multicentre, cluster randomised trial. 
 
5.2 Inclusion criteria 
• Patients 
o All consecutive adult patients aged 18 years and over admitted to 
participating centres undergoing elective and non-elective surgery 
• Participating surgical centres 
o Randomised according to a stratification based upon the level of the 
surgical facility and the surgical case load. Recruitment will run until 
March 2020.   
We plan to randomise 664 hospitals to either increased postoperative surveillance or 
standard care for high-risk adult (≥18 years) surgical patients. The follow up is in-
hospital. This study will be registered on ClinicalTrials.gov. 
 
5.3 Exclusion criteria 
• Prior participation in ASOS-2 
 
5.4 Study flow diagram 
 
Assess eligibility
Adult ≥ 18 years, undergoing in-patient surgery
Randomisation
664 Hospitals
66,400 patients
Intervention hospitals
Increased postoperative care
ASOS Surgical Risk Calculator 
determines high-risk patient
Primary outcome
In-hospital mortality
Secondary outcome
In-hospital composite of severe complications and mortality
Normal postoperative care
ASOS Surgical RIsk Calculator  
determines  NOT high-risk patient
Usual care hospitals
Normal ward care
All patients
Primary outcome
In-hospital mortality
Secondary outcome
In-hospital composite of severe complications and mortality

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6. Trial procedures 
 
6.1 Recruitment and screening 
This is a pragmatic trial. It is an African, international cluster randomised controlled 
trial in several African countries. Participating surgical sites will be randomised to 
either increased postoperative surveillance or usual postoperative care. We expect all 
consecutive adult patients aged 18 years and over admitted to participating centres 
undergoing elective and non-elective surgery to be included in the trial. ‘Broadcasting’ 
through appropriate hospital notices and signage will inform the patients and the public 
that the hospital is participating in the cluster randomised trial.   
 
6.2 Informed consent and trial participation 
The requirement for informed patient consent is expected to vary according to 
regulations of the participating nations. The national leaders will ensure ethics approval 
is obtained from their respective countries and centres prior to participation. 
  
We will apply to all ethics committees for a waiver of consent for participating trial sites 
for the following reasons. Firstly, more than 50% of surgery in Africa is urgent or 
emergent, and urgent or emergent surgent is a strong independent predictor of 
postoperative mortality in Africa.8 Attempts to obtain traditional consent in the 
preoperative period in predominantly urgent and emergent surgery, which may include 
patients with a decreased level of consciousness may lead to non-consecutive patient 
enrolment in the ASOS-2 Trial. It is likely that this would lead to a biased sample, with 
artificially low estimates of adverse outcomes in African surgical patients, and data 
following the trial which are not generalisable to the majority of African surgical 
patients. Secondly, for these reasons, a waiver of consent is increasingly common 
around the world in both interventional and observational research involving time-
sensitive procedures, such as surgery. Thirdly, generating biased and poorly 
generalizable data would not address the research question, and thus would dishonour 
the contributions of the other included patients, and would be wasteful research, in a 
resource-limited environment. Fourthly, we believe that the trial intervention is low 
risk. Furthermore, the patients in the control arm will receive the current standard 
postoperative care. The intervention group will receive a low risk intervention which is 
only aimed at increasing surveillance of at-risk patients. Finally, we would use 
‘broadcasting’ at participating sites to ensure that all patients and family members were 
aware that the surgical site was a participating surgical trial site, through appropriate 
signage (appendix 2). 

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6.3. 
Randomisation 
Participating sites will be randomised to normal postoperative care (“SOC”), or 
increased postoperative surveillance (“Intervention”) in four recruitment blocks 
(calendar time blocks). Randomisation in each block will be stratified by country and by 
level of the surgical facility with a fixed block size of 2. The randomisation algorithm will 
seek to balance randomisation arms by simulating randomisations with an automated 
filter to screen out poorly balanced randomisations. In the second and subsequent 
recruitment blocks, the randomisation algorithm will use knowledge of the previous 
randomisations and a similar simulation and filtering approach to ensure reasonable 
balance across arms and across level of surgical facility. This approach was developed 
on the basis of a simulation model for the randomisation that was used to evaluate the 
probability of overall balance of randomisation arms and balance within level of care 
strata if randomising recruitment phases in waves. Results of 10,000 simulation runs 
indicated that a balanced simulation within the bounds described below would be 
obtained >50% of the time without the filtering step.  
 
The algorithm is described briefly here:   
For recruitment phase 1:  
1. Simulate stratified block randomisation within country and level of facility 
2. Check that simulated randomisation has percent SOC between [48% - 52%] 
3. If NO, then repeat steps 1 and 2. If YES then use this randomisation.  
For all other recruitment phases: 
1. Simulate stratified block randomisation for this phase within country and level of 
facility 
2. Combine this simulation with prior actual randomisations 
3. Check that combined randomisation has percent SOC between [48% - 52%] 
4. If NO, then repeat steps 1-3. If YES proceed to next check. 
5. Check that combined randomisation has balance within level of care between 
[45% - 55%]  
6. If NO, then repeat steps 1-5. If YES then use this randomisation. 
 
6.4. 
Trial intervention 
The intervention arm to which each participating site is randomised will be offered to 
all eligible surgical patients for the duration of the trial. 
 
Intervention arm 
Participating sites which have been randomised to increased surveillance will need to 
provide increased surveillance to surgical patients with a predicted increased 

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postoperative risk as determined by the ASOS Surgical Risk Calculator9 stratification 
tool (also available at www.asos.org.za). Increased postoperative surveillance can 
include any of the following; i) admission to a higher care ward than had been planned 
at the time of surgery, ii) an increase in the frequency of nursing observations in the 
postoperative period, iii) ensuring that the patient is assigned to a bed in view of the 
nursing station, and not in a remote location in the postoperative ward, or iv) allowing 
family members to stay with the patient in the ward in the postoperative period. The 
nature of the offered increased postoperative surveillance will be left to the discretion 
of the healthcare workers and the participating sites. However, all sites will be 
encouraged to include more than one of the increased postoperative surveillance 
intervention. The healthcare providers will also receive information on the leading 
causes of postoperative mortality in African surgical patients as documented in ASOS; 
surgical site infections, bloodstream infection and acute respiratory distress syndrome, 
pneumonia, acute kidney injury, postoperative bleeding, and cardiac arrest.8 This will 
be known as the ‘Postoperative surveillance bedside guide’ and will be placed at the 
bedside of every patient flagged as high-risk by the ASOS Surgical Risk Calculator.9 This 
should be placed in a visible position at the patient’s bedside e.g. posted on the wall 
above the patient’s bed. 
 
Control arm 
Participating sites randomised to the control arm will provide usual postoperative care 
to patients. The care will be left to the discretion of the healthcare providers.  
 
6.5. 
Data collection and collation 
Dataset 
This is a pragmatic trial in a resource-limited environment. As a result, a realistic data 
set will be fundamental to the success of the trial. We are confident that the proposed 
data set will achieve this objective, as it is smaller than the data sets used in ASOS,8 the 
European Surgical Outcomes Study (EuSOS),3 and the International Surgical Outcomes 
Study (ISOS),10 and these studies successfully achieved follow up on >95% of patients 
despite requiring data on all surgical patients at each participating centre for a week of 
surgery. We believe that these key data points will encourage centres to participate as 
there will not be an excessive burden of data collection.  
 
Centre-specific data will be collected once for each hospital including: university or non-
university hospital, number of hospital beds, number of operating rooms, number and 
level of critical care beds and details about the reimbursement status of the hospital. 
 

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An ASOS-2 case record form (CRF) will be completed for every eligible patient who 
undergoes surgery during the trial (appendix 3). 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. 
 
6.6. 
Predefined protocol violation 
A protocol violation will be defined as patients who were randomised to increased 
surveillance, but did not get any of the planned increased postoperative surveillance 
interventions. 
 
6.7. 
Follow up procedures 
Follow-up data will be collected by a site trial investigator. Investigators will review a 
participant’s in-hospital medical records (paper or electronic) up to hospital discharge. 
6.8. 
Schedule of assessment 
Event/ visit 
Screening 
Pre-
op 
Daily 
postop 
Hospital 
discharge 
Inclusion/ exclusion criteria 
X 
 
 
 
Demographic information 
 
X 
 
 
Medical history 
 
X 
 
 
Preoperative risk stratification, using the ASOS 
Surgical Risk Calculator9 
 
X 
 
 
Review of postoperative surveillance 
 
 
X 
X 
Outcome assessment 
 
 
 
X 
End of trial form 
 
 
 
X 
 
 

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7. Statistical considerations 
 
7.1. 
Sample size calculation 
This is a cluster randomised trial of hospitals in Africa. We will match hospitals on 
expected surgical volume in a week of surgery. This varied tremendously across the 
ASOS group; with a median number of surgical procedures per hospital for the study 
week in ASOS of 29 (IQR 10-71).8 The variability of the individual patient outcomes 
explained by the cluster (or surgical site) is taken into account in these sample size 
calculations. The intra-cluster correlation coefficient (ICC) in ASOS was 0.01. For the 
sample size calculation, we have therefore used a conservative ICC of 0.015. 
 
Based on ASOS, we estimate the coefficient of variance for a 4-week recruitment period 
to be 0.63.  A 4-week recruitment period is defined as the following; i) hospitals stop 
recruiting at the end of the week in which they have exceeded 100 enrolled patients, 
and ii) if a site had not reached 100 enrolled patients after 4 weeks of recruiting, it 
would stop recruiting. 
 
The incidence of mortality in ASOS was 2.1%.8 We expect a 25% relative risk reduction 
in mortality through increased surveillance of postoperative surgical patients at high-
risk of severe complications or in-hospital mortality. Based on the intra-cluster 
correlation coefficient (ICC) for the composite of severe complications and mortality in 
ASOS-2 of 1.5%, a coefficient of variance of 0.63, and stratification for the level of the 
surgical facility, and the volume of procedures per week, a trial for efficacy of increased 
postoperative surveillance would require 64,200 patients, from 642 surgical centres 
across Africa (Table 1).8 Based on a relative risk reduction of 25% in the intervention 
arm, the sample sizes for the primary outcome are shown in Table 1.  
TABLE 1: Sample size calculations for the ASOS-2 Trial based on a power of 80%, 2-sided 
α = 0.05 and a mean cluster size of 100 patients 
Primary outcome (in-hospital all-cause mortality)  
 
Control 
event 
rate 
Intervention 
arm 
 
Relative 
risk 
Intra-cluster 
correlation 
coefficient 
(ICC) 
Coefficient of 
variance 
(CV) 
Total clusters 
2.0% 
1.5% 
0.75 
0.015 
0 
536 
2.0% 
1.5% 
0.75 
0.015 
0.63 
664 
2.0% 
1.6% 
0.80 
0.015 
0.63 
 
1068 

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During the trial an external auditor (Paul Myles) will check the event rate in the control 
arm of the study once 80% of all recruited patients have been captured on REDCap 
(practically this will take place around September 2019). The external auditor will use 
the event rate in the control arm to decide whether recruitment should continue 
beyond the target of 664 hospitals, and for how many months recruitment should 
continue. This specified interim analysis of data will not lead to adjustment of the 
prespecified alpha of 0.05. 
7.2. 
Statistical analysis 
Outcomes will be presented at a continental level. All institutional level data will be 
anonymised prior to publication. 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 
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.  
 
The primary outcome will be in hospital mortality. Overall differences in in-hospital 
mortality will be compared between the intervention and control clusters. All analyses 
will account for clusters. A list of baseline risk factors (the risk factors in the ASOS 
Surgical Risk Calculator) will be included in the analysis. We will use logistic regression 
model to estimate the effect of increased postoperative surveillance, on the primary and 
secondary outcomes.  We will calculate the odds ratios and their associated 95% 
confidence intervals.  We will infer statistical significance if the computed 2-sided p-
value is < 0.05.  A single final analysis is planned at the end of the study.  
 
The detailed statistical analysis plan was added on 19 March 2020 and is attached as 
Appendix 6 to this document.  
7.3. 
Secondary studies 
The use of the ASOS-2 Trial data for secondary studies will be encouraged. 
During the conduct of the ASOS-2 trial we will perform a concurrent process evaluation 
to gain insight into the implementation process. The process evaluation aims to:  
1. 
Measure protocol compliance (fidelity of implementation) 
2. 
Identify factors that influence success of implementation  
3. 
Verify specified process steps that form part of the implementation of the 
protocol and logical framework of the trial 
4. 
Generate contextual information about the trial setting  
The questions asked by the process evaluation are:  

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1. 
Which factors determined fidelity of implementation at the local hospital level?  
2. 
How did implementation of the intervention affect patient care? 
3. 
Why does the intervention produce (or fail to produce) a change in patient 
morbidity and mortality?  
 
The measurement tools used for the process evaluation are:  
1. 
The post-education, REDCap based, online test  
2. 
The individual participant case report form (CRF), 
3. 
An online database, called the screening log, which is a REDCap application for 
participating hospitals to record the number of eligible patients daily,   
4. 
Research fellows will perform selected site visits in order to verify specified 
process steps and perform structured interviews with a sample of stakeholders,  
5. 
Telephonic structured interviews with a sample of stakeholders that cannot be 
reached by the two research fellows 
6. 
A post-trial, semi-quantitative, REDCap based, online questionnaire built around 
the key components identified in the structured interviews and the pilot trial 
 
Each member of the local hospital investigator team will be asked to complete the post-
education online test prior to patient recruitment. The online test comprises eight short 
multiple-choice questions which checks comprehension of the key points from the 
education material.   
The individual participant CRF (appendix 3) captures information that allows checking 
accuracy of risk stratification, fidelity of implementation, and differences in patient 
experience between non-high risk patients in the two arms.  
The research fellows will visit specific sites during the trial on appointed days agreed 
upon by the local hospital investigators. They will visit sites during the initiation phase, 
the recruitment phase, and the follow-up phase of the trial. They will use standard site 
visit checklists to identify non-compliance, barriers and facilitators of implementation. 
During the follow-up phase they will interview a qualitative sample of stakeholders who 
indicate willingness to participate in an interview about their personal experience of the 
trial. Interviews will be recorded. Verbal consent will be obtained and recorded for each 
interviewee who agrees to participate. No personal identifying information will be 
recorded for interviewees. A semi-structured script will be used for the interviews. 
Recordings will be stored on a cloud base, password protected drive uploaded by the 
interviewers.  Interviews will be analysed deductively by independent investigators 
using the Consolidated Framework for Implementation Research (CFIR) as a guide.  
The post-trial questionnaire will be anonymous. At the start of the questionnaire 
respondents will be informed about its content and intent. Respondents will be given 
the opportunity to opt out, or to give consent prior to continuing to the questions. 

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Questions will test the CFIR constructs that were highlighted in the structured 
stakeholder interviews.  
8. Research ethics 
 
8.1 Ethical principles 
 
The PI will ensure that this trial is conducted in accordance with the Principles of the 
Declaration of Helsinki as amended in Tokyo (1975), Venice (1983), Hong Kong (1989), 
South Africa (1996), Edinburgh (2000), Washington DC (2002), Tokyo (2004), Seoul 
(2008) and Fortaleza (2013) and adopted by the World Medical Association in 2017 as 
described at the following internet site: https://www.wma.net/policies-post/wma-
declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-
subjects/ .  In South Africa, the trial will be conducted according to the Department of 
Health guidelines: ‘Ethics in Health Research: principles, processes and structures 2nd 
edition’, published in 2015. 
Research ethics and regulatory approvals will be sought before starting the trial at each 
site, in accordance with national research legislation/guidelines for that country. This 
may require the translation of the trial protocol and ‘broadcasting’ documents. Other 
trial documents will be translated at the discretion of the national lead investigator. Full 
approval by the Research Ethics Committee will be obtained prior to starting the trial 
and fully documented by letter to the Chief Investigator naming the trial site, local PI 
(who may also be the Chief Investigator) and the date on which the ethics committee 
deemed the trial as permissible at that site. All members of the trial steering committee 
will declare conflicts of interest before joining the study group. These will be listed on 
any publications arising from the trial. 
 
 

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9. Data handling and record keeping 
 
Data will be collected in individual centres on paper case record forms (CRFs). 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 outcomes. Data will then be pseudo-
anonymised by generation of a unique numeric code and transcribed by local 
investigators onto an 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. Data were anonymised during the transcription 
process using REDCap (Research Electronic Data Capture) tools hosted by Safe Surgery 
South Africa. REDCap is a secure, web-based application designed to support data 
capture for research studies.11 
 
Where individual centres are unable to access the internet-based case record form, 
pseudo-anonymised (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 co-ordinating centre if necessary. 
 
Each centre will complete a screening log reporting the number of eligible surgical 
patients who had surgery during the trial at the centre. 
 
Each centre will maintain a secure trial file including a protocol, local investigator 
delegation log, ethics approval documentation, and the patient list.  
 
Once the local co-ordinator confirms data entry is complete for their hospital they will 
receive a spreadsheet of raw (un-cleaned) data, allowing further checks for data 
completeness and accuracy. 
 
 

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10. Monitoring and auditing 
 
The Sponsor will have oversight of the trial conduct at each site. The trial team will take 
day-to-day responsibility for ensuring compliance with the requirements of GCP in 
terms of quality control and quality assurance of the data collected as well as safety 
reporting. The ASOS-2 Trial Management Group will communicate closely with 
individual sites and the Sponsor’s representatives to ensure these processes are 
effective. A Data and Safety Monitoring Board (DSMB) will be not be appointed for this 
trial. The reasons for this decision are discussed in section 11.3 on page 19. 
 
However, an independent international advisor has been appointed to the ASOS-2 Trial 
(Prof Paul Myles). Should the recruitment target have not been met during the trial, his 
role will be to determine whether; i) hospital recruitment can continue after the 
planned recruitment window, and ii) whether an interim analysis would be required 
prior to continuing recruitment.  
 
10.1 Training of investigators 
All investigators will complete training consistent with their national regulations for 
clinical research, as well as those in the country of the trial sponsor (RSA). A 
representative of the national coordinating centre for that country will conduct a site 
initiation at each site before patient recruitment commences, or conduct a remote 
electronic site initiation. The site initiation will include an induction to the trial protocol 
and procedures, the standardised assessment of outcome measures, and the trial 
database. When new investigators join the research team at a particular site during the 
course of the trial, the responsibility for induction training will fall to the local principal 
investigator. 
 
10.2 Monitoring the safety and wellbeing of trial participants 
Systems are in place to ensure that all PIs and designees are able to demonstrate that 
they are qualified by education, training or experience to fulfil their roles and that 
procedures are in place that assures the quality of every aspect of the trial.  
Based on the expected rapidity of completion of the trial from initiation, it will not be 
possible to terminate the trial early. We believe that this is acceptable considering the 
low risk of the trial intervention. Day to day management and monitoring of individual 
sites will be undertaken via the Trial Management Group composed of the Chief 
Investigator and supporting staff. They will meet on a regular basis to discuss trial 
issues.  

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11. Trial management and committees 
 
11.1 Trial management group 
Day-to-day trial management will be co-ordinated by a trial management group 
consisting of the Chief Investigator and his/her support staff. 
 
11.2 Trial Steering Committee 
The Trial Steering Committee will oversee the trial and will consist of: 
• several independent clinicians and trialists 
• co-investigators (including a representative of each participating nation) 
 
Meetings will be held at regular intervals determined by need but not less than once a 
year. The TSC will take responsibility for: 
• approving the final trial protocol; 
• major decisions such as a need to change the protocol for any reason; 
• monitoring and supervising the progress of the trial; 
• reviewing relevant information from other sources; 
• informing and advising on all aspects of the trial 
 
11.3 Data and Safety Monitoring Board 
The principle responsibility of a Data and Safety Monitoring Board (DSMB) is to 
safeguard the interests of trial participants, including assessing the safety of the 
intervention, reviewing relevant new external evidence, and monitoring the overall 
conduct of the trial. A DSMB provides recommendations about stopping, modifying or 
continuing the trial to the Trial Steering Committee.  
The ASOS-2 Trial will not appoint a DSMB. The reasons for not appointing a DSMB are 
the following; i) the intervention is considered of a low risk (and the DSMB functions 
primarily to identify increased adverse events associated with the intervention), and ii) 
the trial is expected to be completed within two months of initiation at a site, and all 
sites will recruit within a four-month window period. It is therefore unlikely that 
sufficient data will be available to allow for an interim analysis and a decision to be 
made on the analysis, prior to the completion of the trial. We are confident that the trial 
could be completed within two months, as in ASOS the median surgical volume was 29 
patients per week,8 and each hospital in the ASOS-2 Trial is expected to recruit 100 
patients within a four week period. 

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12. Data management and ownership 
 
On behalf of the Steering Committee, Safe Surgery South Africa (SSSA) will act as 
custodian of the data. 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 conduct secondary analyses. 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 institutional and patient level data will be strictly 
anonymised. Individual patient data provided by participating hospitals remain the 
property of the respective institution. Once each local co-ordinator has confirmed the 
data provided from their hospital are both complete and accurate, they will be provided 
with a spreadsheet of the raw (un-cleaned) data for their hospital. 
The complete ASOS-2 dataset, anonymised with respect to participating patients and 
hospitals, will be made freely and publicly available two years following publication of 
the main scientific report. Prior to this, the steering committee is not under any 
obligation to release data to any collaborator or third party if they believe this is not in 
keeping with the wider aims of the ASOS-2 project. 
 
 
 

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13. Publication plan and public communication of trial results 
 
The Steering Committee will appoint a writing committee to draft the scientific 
report(s) of this investigation, which will be disseminated in a timely manner. The 
group will be known as ‘The ASOS-2 Investigators’. It is anticipated that a number of 
secondary analyses will be performed. ASOS-2 investigators will be given priority to 
lead such analyses and are encouraged to do so. Participation and authorship 
opportunities will be based on contribution to the primary study. 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 necessary, a prior 
written agreement will set out the terms of such collaborations. The steering committee 
must approve the final version of all manuscripts including ASOS-2 data prior to 
submission. In the event of disagreement within the steering committee, the Chief 
Investigator will make a final ruling. Any analysis incorporating ASOS-2 data from two 
or more study sites will be considered a secondary analysis and subject to these rules. 
The Steering Committee must approve the final version of all manuscripts prior to 
submission, whether they relate to part or all of the ASOS-2 dataset. 
 
In order to inform the participating communities of the results, the ASOS-2 Trial results 
and possible interventions to improve postoperative surgical mortality will also be 
broadcast using appropriate signage at the facilities that participated in the trial. 

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References 
 
1. Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: a 
modelling strategy based on available data. Lancet 2008;372(9633):139-44. doi: 
10.1016/S0140-6736(08)60878-8 [published Online First: 2008/06/28] 
2. Devereaux PJ, Chan MT, Alonso-Coello P, et al. Association between postoperative troponin levels 
and 30-day mortality among patients undergoing noncardiac surgery. Jama 
2012;307(21):2295-304. doi: 10.1001/jama.2012.5502 [published Online First: 2012/06/19] 
3. Pearse RM, Moreno RP, Bauer P, et al. Mortality after surgery in Europe: a 7 day cohort study. 
Lancet 2012;380(9847):1059-65. doi: 10.1016/S0140-6736(12)61148-9 [published Online 
First: 2012/09/25] 
4. Chao TE, Sharma K, Mandigo M, et al. Cost-effectiveness of surgery and its policy implications for 
global health: a systematic review and analysis. Lancet Glob Health 2014;2(6):e334-45. doi: 
10.1016/s2214-109x(14)70213-x [published Online First: 2014/08/12] 
5. Grimes CE, Henry JA, Maraka J, et al. Cost-effectiveness of surgery in low- and middle-income 
countries: a systematic review. World J Surg 2014;38(1):252-63. doi: 10.1007/s00268-013-
2243-y [published Online First: 2013/10/09] 
6. Dare AJ, Grimes CE, Gillies R, et al. Global surgery: defining an emerging global health field. Lancet 
2014;384(9961):2245-7. doi: 10.1016/S0140-6736(14)60237-3 [published Online First: 
2014/05/24] 
7. Meara JG, Leather AJ, Hagander L, et al. Global Surgery 2030: evidence and solutions for achieving 
health, welfare, and economic development. Lancet 2015;386(9993):569-624. doi: 
10.1016/S0140-6736(15)60160-X 
8. Biccard BM, Madiba TE, Kluyts HL, et al. Perioperative patient outcomes in the African Surgical 
Outcomes Study: a 7-day prospective observational cohort study. Lancet 
2018;391(10130):1589-98. doi: 10.1016/S0140-6736(18)30001-1 [published Online First: 
2018/01/08] 
9. Kluyts HL, le Manach Y, Munlemvo DM, et al. The ASOS Surgical Risk Calculator: development and 
validation of a tool for identifying African surgical patients at risk of severe postoperative 
complications. Br J Anaesth 2018;121(6):1357-63. doi: 10.1016/j.bja.2018.08.005 [published 
Online First: 2018/11/18] 
10. International Surgical Outcomes Study g. Global patient outcomes after elective surgery: 
prospective cohort study in 27 low-, middle- and high-income countries. Br J Anaesth 
2016;117(5):601-09. doi: 10.1093/bja/aew316 [published Online First: 2016/11/02] 
11. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)--a metadata-
driven methodology and workflow process for providing translational research informatics 
support. J Biomed Inform 2009;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010 
  
 
 

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Appendix 1 
 
African Surgical OutcomeS-2 (ASOS-2) Trial: Definitions document 
 
 

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Definitions document 
 
Table of Contents 
Definitions of preoperative risk factors ............................................................................................ 28 
What is the definition of neurosurgery? ........................................................................................ 28 
What should I do if some important medical co-morbidities are not included on the case 
record form (CRF)? ......................................................................................................................... 28 
What are the definitions of the chronic co-morbid diseases?...................................................... 28 
American Society of Anesthesiologists (ASA) score ..................................................................... 28 
Urgency of surgery .......................................................................................................................... 28 
Severity of the surgery .................................................................................................................... 28 
Definitions of postoperative care ....................................................................................................... 30 
Post anaesthesia care unit (PACU): ................................................................................................ 30 
High care ward: ............................................................................................................................... 30 
Increased frequency of nursing observations: .............................................................................. 30 
Patient’s bed in view of the nurses’ station: .................................................................................. 30 
Family members to stay with the patient in the ward: ................................................................ 30 
Definitions of severe surgical complications .................................................................................... 31 
Surgical site infection (superficial) ................................................................................................ 31 
Surgical site infection (deep) .......................................................................................................... 31 
Surgical site infection (organ/space)............................................................................................. 32 
Bloodstream infection ..................................................................................................................... 32 
Acute Respiratory Distress Syndrome (ARDS) ............................................................................. 33 
Pneumonia ....................................................................................................................................... 33 
Urinary tract infection .................................................................................................................... 34 
Acute Kidney Injury (AKI) .............................................................................................................. 34 
Postoperative haemorrhage ........................................................................................................... 34 
Cardiac arrest .................................................................................................................................. 34 
Other severe complications ............................................................................................................ 34 
Anastomotic breakdown ................................................................................................................. 34 
Arrhythmia....................................................................................................................................... 35 
(Cardiogenic) pulmonary oedema ................................................................................................. 35 
Gastro-intestinal bleed .................................................................................................................... 35 

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Myocardial infarction ...................................................................................................................... 35 
Pulmonary embolism (PE) ............................................................................................................. 35 
Stroke ............................................................................................................................................... 35 
Hospital resource use after surgery ................................................................................................... 36 
Critical care admission to treat postoperative complications: .................................................... 36 
Days in hospital after surgery: ....................................................................................................... 36 
Status at hospital discharge or 30th postoperative in-hospital day: ............................................ 36 
Reference ............................................................................................................................................. 36 
 
 
 

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Definitions of preoperative risk factors 
 
What is the definition of neurosurgery? 
Neurosurgical procedures are defined as involving the brain and cervical spine. Surgery 
on the thoracic and lumbar spine is defined as orthopaedic surgery in the CRF. 
  
What should I do if some important medical co-morbidities are not 
included on the case record form (CRF)? 
We realise that some patients may have important data which we have not asked for. 
The CRF has been designed to request only the most important patient data. 
  
What are the definitions of the chronic co-morbid diseases? 
We have not made any definitions for these diseases. We simply want doctors to give 
what they believe are the most appropriate answers. If the patient probably has the 
disease, then tick the box. If they probably do not have the disease, then leave it blank. 
 
American Society of Anesthesiologists (ASA) score 
I    A normal healthy patient 
II   A patient with mild systemic disease which does not limit physical activity 
III  A patient with severe systemic disease which limits physical activity 
IV  A patient with severe systemic disease that is a constant threat to life 
V   A patient who is not expected to survive for 24 hours without the operation. 
 
 
Urgency of surgery 
  
Elective: Not immediately life-saving; planned within months or weeks. 
  
Urgent: Planned surgery within hours or days of the decision to operate. 
  
Emergency: As soon as possible; no delay to plan care; ideally within 24 hours. 
  
 
Severity of the surgery 
 
This is the category of surgery which indicates a combination of complexity and amount 
of tissue injury. 

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Minor surgery would include procedures lasting less than 30 minutes performed in a 
dedicated operating room which would often involve extremities or body surface or 
brief diagnostic and therapeutic procedures eg arthroscopy without intervention, 
removal of small cutaneous tumour, diagnostic proctology, biopsy of small lesions, etc. 
  
Intermediate procedures are more prolonged or complex that may pose the risk of 
significant complications or tissue injury. Examples include laparoscopic 
cholecystectomy, arthroscopy with intervention, bilateral varicose vein removal, 
tonsillectomy, inguinal hernia repair, breast lump resection, haemorrhoidectomy, 
appendicectomy, partial thyroidectomy, cataract surgery, uvuloplasty, minimally 
invasive repair of vaginal prolapse, vaginal hysterectomy, tendon repair of hand, 
fixation of mandibular fracture, etc. 
  
Major surgical procedures are expected to last more than 90 minutes and include major 
gut resection, major joint replacement, mastectomy, extensive head and neck tumour 
resection, abdominal aortic aneurysm repair, major vascular bypass procedure, 
procedures involving free flap to repair tissue defect, amputation, total thyroidectomy, 
cystectomy, trans-urethral resection of prostate, resection of liver tumour, carotid 
endarterectomy, nephrectomy, total abdominal hysterectomy, spinal discectomy, etc. 
 
 
 
 

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Definitions of postoperative care  
 
Post anaesthesia care unit (PACU):  
A postoperative recovery ward or unit which is dedicated to providing increased 
postoperative care during recovery (both in intensity of monitoring and in duration of 
care), when compared to normal postoperative recovery care. 
 
High care ward:  
A postoperative ward which is dedicated to providing increased postoperative care, 
when compared to the normal postoperative surgical ward. 
 
Increased frequency of nursing observations:  
Nursing observations which are conducted more frequently, than the normal frequency 
of observations on the postoperative ward.  
 
Patient’s bed in view of the nurses’ station:  
The patient is positioned in a bed close to the nursing station to ensure that the nurses 
can always see the patient from the nursing station. 
 
Family members to stay with the patient in the ward:  
If the family members are asked to stay with the patient on the ward, because of a 
concern that the patient is at increased risk of death of morbidity in the postoperative 
period. 
 
 
 
 
 

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Definitions of severe surgical complications  
 
The following definitions and grading are provided for guidance where the nature and 
severity of a possible complication following surgery is uncertain. These definitions are 
based on the ‘Standards for definitions and use of outcome measures for clinical 
effectiveness research in perioperative medicine: European Perioperative Clinical 
Outcome (EPCO) definitions: a statement from the ESA-ESICM joint taskforce on 
perioperative outcome measures’.1  
 
Definition of a ‘Severe Complication’ 
Results in significant prolongation of hospital stay and/or permanent functional 
limitation or death. Almost always requires clinical treatment. 
 
Surgical site infection (superficial)  
Infection involving only superficial surgical incision which meets the following criteria:  
1. Infection occurs within 30 days after surgery and  
2. Involves only skin and subcutaneous tissues of the incision and  
3. The patient has at least one of the following:  
a. purulent drainage from the superficial incision  
b. organisms isolated from an aseptically obtained culture of fluid or tissue 
from the superficial incision and at least one of the following signs or 
symptoms of infection: pain or tenderness, localized swelling, redness, or 
heat, or superficial incision is deliberately opened by surgeon and is 
culture positive or not cultured. A culture-negative finding does not meet 
this criterion.  
c. diagnosis of a incisional surgical site infection by a surgeon or attending 
physician  
 
Surgical site infection (deep)  
An infection which involves both superficial and deep parts of surgical incision and 
meets the following criteria:  
1. Infection occurs within 30 days after surgery if no surgical implant is left in place 
or one year if an implant is in place and  
2. The infection appears to be related to the surgical procedure and involves deep 
soft tissues of the incision (e.g. fascial and muscle layers) and  
3. The patient has at least one of the following:  

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a. purulent drainage from the deep incision but not from the organ/space 
component of the surgical site  
b. a deep incision spontaneously dehisces or is deliberately opened by a 
surgeon and is culture-positive or no cultures were taken whilst the 
patient has at least one of the following signs or symptoms of infection: 
fever (>38°C) or localized pain or tenderness. A culture-negative finding 
does not meet this criterion.  
c. an abscess or other evidence of infection involving the deep incision is 
found on direct examination, during surgery, or by histopathologic or 
radiologic examination  
d. diagnosis of a deep incisional surgical site infection by a surgeon or 
attending physician  
 
Surgical site infection (organ/space)  
An infection which involves any part of the body excluding the fascia or muscle layers 
and meets the following criteria:  
1. Infection occurs within 30 days after surgery and  
2. The infection appears to be related to the surgical procedure and involves any 
part of the body, excluding the skin incision, fascia, or muscle layers, that is 
opened or manipulated during the operative procedure and  
3. The patient has at least one of the following:  
a. purulent drainage from a drain that is placed through a stab wound into 
the organ/space  
b. organisms isolated from an aseptically obtained culture of fluid or tissue 
in the organ/ space  
c. an abscess or other evidence of infection involving the organ/space that is 
found on direct examination, during reoperation, or by histopathologic or 
radiologic examination  
d. diagnosis of an organ/space surgical site infection by a surgeon or 
attending physician  
 
 
Bloodstream infection  
An infection which is not related to infection at another site and which meets at least 
one of the following criteria:  
1. Patient has a recognised pathogen cultured from blood cultures which is not 
related to an infection at another site  

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2. Patient has at least one of the following signs or symptoms: fever (>38°C), chills, 
or hypotension and at least one of the following:  
a. common skin contaminant cultured from two or more blood cultures 
drawn on separate occasions  
b. common skin contaminant cultured from at least one blood culture from a 
patient with an intravascular line, and a physician starts antimicrobial 
therapy  
c. positive blood antigen test  
 
Acute Respiratory Distress Syndrome (ARDS)  
Respiratory failure, or new or worsening respiratory symptoms, commencing within 
one week of surgery; and a chest radiograph or computed tomography scan which 
demonstrates bilateral opacities not fully explained by effusions, lobar/lung collapse, or 
nodules; and respiratory failure not fully explained by cardiac failure or fluid overload. 
Need objective assessment (e.g. echocardiography) to exclude hydrostatic oedema if no 
risk factor is present.  
 
Severity grading:  
Severe: PaO2:FiO2 ≤100 mmHg with PEEP ≥5 cmH2O  
 
Guidance:  
If altitude is higher than 1000 m, a correction factor should be calculated as follows: 
(PaO2:FiO2 x [barometric pressure/760 mmHg]). PEEP, positive end-expiratory 
pressure; CPAP, non-invasive continuous positive airways pressure 
 
Pneumonia 
Chest radiographs with new or progressive and persistent infiltrates, or consolidation, 
or cavitation, and at least one of the following: 
1. fever (>38°C) with no other recognized cause 
2. leucopaenia (<4,000 white blood cells/mm3) or leucocytosis (>12,000 white 
blood cells/mm3) 
3. for adults >70 years old, altered mental status with no other recognised cause; 
and at least two of the following: 
1. new onset of purulent sputum or change in character of sputum, or increased 
respiratory secretions, or increased suctioning requirements  
2. new onset or worsening cough, or dyspnoea, or tachypnoea 
3. rales or bronchial breath sounds 
4. worsening gas exchange (hypoxaemia, increased oxygen requirement or 
increased ventilator demand) 
 

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Guidance: Two radiographs are required for patients with underlying pulmonary or 
cardiac disease. The definition may be used to identify ventilator associated pneumonia. 
 
Urinary tract infection  
An infection associated with at least one of the following signs or symptoms which 
should be identified within a 24 hour period; fever (>38 °C), urgency, frequency, 
dysuria, suprapubic tenderness, costovertebral angle pain or tenderness with no other 
recognised cause,  
and a positive urine culture of ≥105 colony forming units/mL with no more than two 
species of microorganisms. 
  
Acute Kidney Injury (AKI) 
 
Acute Kidney Injury 
(AKI) Stage  
Serum creatinine  
Urine output  
Severe  
Increase of 3.0 times 
baseline within 7 days or 
increase in serum 
creatinine to ≥4.0 mg/dL 
(≥354 μmol/L) with an 
acute rise of >0.5 mg/dL 
(>44 μmol/L) or initiation 
of renal replacement 
therapy  
≤0.3 ml/kg/h for 24 hours  
or  
Anuria for 12 hours  
 
 
Guidance: Baseline serum creatinine must be measured before surgery but an 
estimated value can be used if the patient does not have chronic kidney disease. 
Postoperative haemorrhage  
Blood loss occurring within 72 hours after the end of surgery which would normally 
result in transfusion of blood. 
 
Cardiac arrest  
The cessation of cardiac mechanical activity, as confirmed by the absence of signs of 
circulation. ECG changes may corroborate the incidence of cardiac arrest.  
 
Other severe complications 
If any of the following complications result in a significant prolongation of hospital stay 
and/or permanent functional limitation or death, then mark ‘Other severe complication’ 
as ‘Yes’. Note that they will almost always requires clinical treatment. 
Anastomotic breakdown  
Leak of luminal contents from a surgical connection between two hollow viscera. The 
luminal contents may emerge either through the wound or at the drain site, or they may 

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collect near the anastomosis, causing fever, abscess, septicaemia, metabolic disturbance 
and/or multiple-organ failure. The escape of luminal contents from the site of the 
anastomosis into an adjacent localised area, detected by imaging, in the absence of 
clinical symptoms and signs should be recorded as a sub-clinical leak.  
 
Arrhythmia  
Electrocardiograph (ECG) evidence of cardiac rhythm disturbance.  
 
(Cardiogenic) pulmonary oedema  
Evidence of fluid accumulation in the alveoli due to poor cardiac function.  
 
Gastro-intestinal bleed  
Unambiguous clinical or endoscopic evidence of blood in the gastro-intestinal tract. 
Upper gastrointestinal bleeding is that originating from the oesophagus, stomach and 
duodenum. Lower gastro-intestinal bleeding originates from the small bowel and colon.  
 
Myocardial infarction  
Increase in serum cardiac biomarker values (preferably cardiac troponin) with at least 
one value above the 99th percentile upper reference limit and at least one of the 
following criteria:  
1. Symptoms of ischaemia  
2. New or presumed new ST-segment or T-wave ECG changes or new left bundle 
branch block  
3. Development of pathological Q-waves on ECG  
4. Radiological or echocardiographic evidence of new loss of viable myocardium or 
new regional wall motion abnormality  
5. Identification of an intra-coronary thrombus at angiography or autopsy  
Pulmonary embolism (PE)  
A new blood clot or thrombus within the pulmonary arterial system.  
 
Guidance: Appropriate diagnostic tests include scintigraphy and CT angiography. 
Plasma D-dimer measurement is not recommended as a diagnostic test in the first three 
weeks following surgery.  
 
Stroke  
Embolic, thrombotic, or haemorrhagic cerebral event with persistent residual motor, 
sensory, or cognitive dysfunction (e.g. hemiplegia, hemiparesis, aphasia, sensory deficit, 
impaired memory).  
 
 
 

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Hospital resource use after surgery  
We will collect some basic data to describe the treatment resources patients received 
after surgery.  
 
Critical care admission to treat postoperative complications: 
Postoperative complications requiring admission to critical care to treat the 
postoperative complications or provide critical care support necessitated by the 
severity of the postoperative complications.  
 
Days in hospital after surgery: Total number of days in hospital after surgery.  
 
Status at hospital discharge or 30th postoperative in-hospital day: The 
survival status of the patient at hospital discharge, or at the 30 in-hospital day (if the 
patient had not yet been discharged following surgery). The study is censored at the 
30th in hospital postoperative day.  
Reference 
1. Jammer I, Wickboldt N, Sander M, et al. Standards for definitions and use of outcome 
measures for clinical effectiveness research in perioperative medicine: European 
Perioperative Clinical Outcome (EPCO) definitions: a statement from the ESA-ESICM 
joint taskforce on perioperative outcome measures. Eur J Anaesthesiol 2015;32(2):88-
105. doi: 10.1097/EJA.0000000000000118 
 
 
 

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Appendix 2 
African Surgical OutcomeS-2 (ASOS-2) Trial: Hospital ‘broadcasting’ signage 
 
 

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Appendix 3 
African Surgical OutcomeS-2 (ASOS-2) Trial: Case Record Form (CRF) (Control 
arm) 
 

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African Surgical OutcomeS-2 (ASOS-2) Trial: Case Record Form (CRF) 
(Intervention arm) 
 

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Appendix 4 
ASOS-2 Surgical Risk Calculator Score Card 
 

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Appendix 5 
‘Increased postoperative surveillance’ bedside guide 
 
 
 
 
 
 
 
 

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Appendix 6 
 
Statistical Analysis Plan 
1. TRIAL OBJECTIVES 
1.1. 
Primary effectiveness objective: 
To determine whether increased postoperative surveillance in high-risk adult surgical patients 
reduces overall in-hospital mortality in adult surgical patients aged 18 years and over in Africa. 
1.2. 
Secondary effectiveness objective: 
To determine whether increased postoperative surveillance in high-risk adult surgical patients 
reduces the overall incidence of the composite of severe in-hospital complications and mortality in 
adult surgical patients aged 18 years and over in Africa. 
 
2. TRIAL OUTCOME EVENTS 
2.1. 
Primary effectiveness outcome for evaluation of increased postoperative 
surveillance for high-risk patients: 
In-hospital death censored at 30 days if the patient is still alive and in-hospital.  
2.2. 
Secondary effectiveness outcome: 
Composite of severe in-hospital complications and death censored at 30 days if the patient is still 
alive and in-hospital. 
Severe complications are:  
I. 
Superficial or deep surgical site, or body cavity infection 
II. 
Bloodstream infection or ARDS 
III. 
Urinary tract or AKI 
IV. 
Cardiac arrest 
V. 
Pneumonia 
VI. 
Postoperative bleed  
VII. 
Other severe complications 
The definitions of all the secondary outcomes are given in the Appendix 1: Definitions document. 
 
 

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3. STATISTICAL AND ANALYTICAL METHODS 
 
3.1 Study design 
The study design is a two arm, cluster randomised trial where randomisation was stratified by 
hospital level (tertiary, secondary, primary) and carried out in waves to permit ongoing recruitment 
of hospitals throughout the duration of the trial.       
3.2. Analysis population 
Primary analysis will be by modified intention to treat population which includes all patients 
recruited from randomised hospitals where the hospital reported any patient data. Hospitals that 
are randomised, but do not submit any patient data will be excluded from the modified intention to 
treat analysis on the presumption that there is no risk of exposure to the trial intervention. Patients 
will be analysed in the treatment group to which their hospitals were originally allocated.  
Secondary analyses will include two analytic approached to two per protocol populations. Refer to 
table: Secondary analyses based on implementation fidelity. In the first per protocol analysis we will 
compare all patients from hospitals with data in the standard of care arm to all patients from 
hospitals with data in the intervention arm where the intervention hospital provided the 
intervention with fidelity to at least 80% of high-risk patients. Patients from hospitals in the 
intervention arm where the hospital delivered the intervention with fidelity to fewer than 80% of 
patients will be excluded from this analysis. In the second per protocol analysis we will compare all 
patients from hospitals with data in the standard of care arm to all patients from hospitals in the top 
two tertiles of implementation fidelity. Patients from intervention hospitals in the bottom tertile of 
implementation fidelity will be excluded from this analysis. At the hospital level we will report 
implementation fidelity as the proportion of high-risk patients who received the intervention with 
fidelity. We use two definitions for implementation fidelity; i) provision of at least the high-risk 
bedside guide plus one additional component of the intervention on days 0 and 1 postoperatively 
and ii) provision of at least 2 components of the intervention on days 0 and days 1 postoperatively, 
regardless whether the high-risk beside guide is one of the components.        
 
 
 
 
 
 
 
 
 

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Bruce Biccard  
19 March 2020 
ASOS-2 Trial protocol v.7 
Secondary analyses based on implementation fidelity 
 
Fidelity = High-risk individuals 
exposed to the bedside guide 
plus at least 1 additional 
component of the intervention 
Fidelity = High-risk individuals 
exposed to at least 2 
components of the 
intervention, regardless 
whether one is the bedside 
guide 
Intervention hospitals where 
>= 80% of high-risk patients 
received the intervention with 
fidelity 
Per protocol analysis 1  
Per protocol analysis 3  
Top two tertiles of intervention 
hospitals ranked according to 
proportion of patients 
receiving the intervention with 
fidelity 
Per protocol analysis 2  
Per protocol analysis 4  
 
3.2. 
Effectiveness analyses 
3.2.1. 
Effectiveness analyses 
Primary outcome 
Relative risk of death in-hospital (within 30d) in the intervention arm vs death in-hospital (within 
30d) in the standard of care arm, estimated by univariable generalised estimating equation under a 
binomial model with a log link and assuming an exchangeable correlation structure. Clustering will 
be assumed to be on hospitals within countries in a fully nested framework.  
Secondary outcome 
Relative risk of death in-hospital or severe complication (within 30d) in the intervention arm vs 
death in-hospital or severe complication (within 30d) in the standard of care arm. Analysis approach 
will be as in primary outcome. 
3.2.2. 
 Sensitivity and subgroup analyses on the effectiveness outcomes 
Sensitivity analysis will investigate the potential for unobserved outcomes (transfer out or lost to 
follow up) to impact primary and secondary effectiveness estimates. Under the same model as the 
primary (secondary) effectiveness outcomes individuals with unobserved outcomes (lost to follow 
up) will alternately be assumed to be alive at discharge (censored at thirty days) or to have died in-
hospital within 30 days. These estimates and confidence intervals will be plotted along with the 
primary (secondary) effectiveness estimates.   
   

45 
 
Bruce Biccard  
19 March 2020 
ASOS-2 Trial protocol v.7 
Primary and secondary endpoints will be analysed under the same model as the primary analysis for 
the following subgroups treated as stratification variables:  
i) 
hospital level (primary,  secondary, tertiary),  
ii) 
duration of recruitment (1,  2 , 3 or 4 weeks) 
iii) 
Calendar time (quarters)  
iv) 
Income category of country (low or middle, according to the World Bank 
classification in 2020)  
 
3.2.3. 
 Patient risk factors and patient level analysis 
A prespecified patient level analysis will be undertaken including all high-risk individuals with data in 
a standard of care hospital, and all high-risk individuals in an intervention arm who can be presumed 
to be exposed to the intervention (definition 1: poster and one other intervention on day 0 and day 
1; definition 2: any 2 interventions on day 0 and day 1). The relative risk of experiencing the primary 
(secondary) outcome by exposure to intervention (as defined above) will be estimated in stratified 
models for the following individual characteristics: 
I. 
age (years) 
II. 
ASA status (1-5) 
III. 
surgical procedure category (Gynaecologic, Obstetric, Neuro, ENT, 
Orthopaedic, Plastics and Breast, Urology, Gastrointestinal and Hepatobilliary, Cardiothoracics, 
Other) 
IV. 
indication for surgery (non-communicable disease, caesarean section, trauma, 
infection) 
V. 
urgency of surgery (elective, urgent, emergent) 
VI. 
severity of surgery (minor, intermediate, major) 
 
This concludes the pre-specified analyses for ASOS-2. Further exploration of the data will take place.