Development of Advanced Double Intravenous Vasopressor Automated (ADIVA) System With Improved Hemodynamic Trend Control During Spinal Anaesthesia for Caesarean Section
Phase: NA
Conditions: Hypotension, Anesthesia
Sponsor: KK Women's and Children's Hospital

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STUDY PROTOCOL 
 
 
Development of advanced double intravenous 
vasopressor automated (ADIVA)system with improved 
hemodynamic trend control during spinal anaesthesia for 
Caesarean section 
 
 
 
PROTOCOL NUMBER: SHF/CTG061/2017 
 
CIRB NUMBER: 2018/2213 
 
PROTOCOL VERSION:  
1.0 
 
PROTOCOL DATE:  2 Aug 2018 
 
PRINCIPAL INVESTIGATOR:  
Dr Singaraselvan Nagarajan, Consultant, Women’s Anaesthesia, KK Women’s And 
Children’s Hospital, 100 Bukit Timah Road, Singapore 229899 
 
 
 
 
 
 
*Refer to Section 9 for determination of sample size, analytical and statistical plan. 
 
 
 
 
 

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Table of Contents 
1 
BACKGROUND AND RATIONALE................................................................................................. 5 
1.1 
GENERAL INTRODUCTION ................................................................................................................... 6 
1.2 
RATIONALE AND JUSTIFICATION FOR THE STUDY ...................................................................................... 7 
1.2.1 
RATIONALE FOR THE STUDY PURPOSE ................................................................................................... 7 
1.2.2 
RATIONALE FOR DOSES SELECTED ........................................................................................................ 8 
1.2.3 
RATIONALE FOR STUDY POPULATION .................................................................................................... 8 
1.2.4 
RATIONALE FOR STUDY DESIGN ........................................................................................................... 9 
2 
HYPOTHESIS AND OBJECTIVES ................................................................................................. 9 
2.1 
HYPOTHESIS ................................................................................................................................... 9 
2.2 
PRIMARY OBJECTIVES ....................................................................................................................... 9 
2.3 
SECONDARY OBJECTIVES ................................................................................................................. 10 
2.4 
POTENTIAL RISKS AND BENEFITS: ...................................................................................................... 10 
2.4.1 
POTENTIAL RISKS .......................................................................................................................... 10 
2.4.2 
POTENTIAL BENEFITS ...................................................................................................................... 11 
3 
STUDY POPULATION ................................................................................................................ 11 
3.1 
LIST THE NUMBER AND NATURE OF SUBJECTS TO BE ENROLLED. ................................................................ 11 
3.2 
CRITERIA FOR RECRUITMENT AND RECRUITMENT PROCESS ....................................................................... 11 
3.3 
INCLUSION CRITERIA ...................................................................................................................... 11 
3.4 
EXCLUSION CRITERIA ...................................................................................................................... 12 
3.5 
SUBJECT REPLACEMENT ................................................................................................................... 12 
4 
STUDY DESIGN ......................................................................................................................... 12 
4.1 
RANDOMISATION AND BLINDING ........................................................................................................ 14 
4.2 
CONTRACEPTION AND PREGNANCY TESTING .......................................................................................... 14 
4.3 
STUDY VISITS AND PROCEDURES ....................................................................................................... 15 
4.3.1 
SCREENING VISITS AND PROCEDURES ................................................................................................. 15 
4.3.2 
STUDY VISITS AND PROCEDURES ....................................................................................................... 15 
4.3.3 
FINAL STUDY VISIT: ....................................................................................................................... 16 
4.3.4 
POST STUDY FOLLOW UP AND PROCEDURES .......................................................................................... 16 
4.4 
DISCONTINUATION/WITHDRAWAL ...................................................................................................... 17 
4.4.1 
DISCONTINUATION CRITERIA ............................................................................................................ 17 
4.4.2 
DISCONTINUATION VISIT AND PROCEDURES ......................................................................................... 17 
5 
TRIAL MATERIALS .................................................................................................................... 17 
5.1 
TRIAL PRODUCT (S) ....................................................................................................................... 17 
5.2 
STORAGE AND DRUG ACCOUNTABILITY ................................................................................................ 17 
6 
TREATMENT .............................................................................................................................. 17 
6.1 
RATIONALE FOR SELECTION OF DOSE .................................................................................................. 17 
6.2 
STUDY DRUG FORMULATIONS ........................................................................................................... 18 
6.3 
STUDY DRUG ADMINISTRATION ......................................................................................................... 18 
6.4 
SPECIFIC RESTRICTIONS / REQUIREMENTS ........................................................................................... 18 
6.5 
BLINDING .................................................................................................................................... 18 
6.6 
CONCOMITANT THERAPY .................................................................................................................. 18 
7 
SAFETY MEASUREMENTS.......................................................................................................... 18 
7.1 
DEFINITIONS ................................................................................................................................ 18 
7.2 
COLLECTING, RECORDING AND REPORTING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS TO CIRB .......... 19 
7.3 
COLLECTING, RECORDING AND REPORTING OF SERIOUS ADVERSE EVENTS (SAES) TO THE HEALTH SCIENCE 
AUTHORITY (HSA) .................................................................................................................................... 20 

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7.4 
SAFETY MONITORING PLAN .............................................................................................................. 20 
7.5 
COMPLAINT HANDLING .................................................................................................................... 20 
8 
DATA ANALYSIS........................................................................................................................ 21 
8.1 
DATA QUALITY ASSURANCE .............................................................................................................. 21 
8.2 
DATA ENTRY AND STORAGE .............................................................................................................. 21 
9 
SAMPLE SIZE AND STATISTICAL METHODS ............................................................................. 21 
9.1 
DETERMINATION OF SAMPLE SIZE ...................................................................................................... 21 
9.2 
STATISTICAL AND ANALYTICAL PLANS ................................................................................................. 21 
10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................................... 22 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 22 
12 
ETHICAL CONSIDERATIONS ..................................................................................................... 22 
12.1 
INFORMED CONSENT....................................................................................................................... 22 
12.2 
CONFIDENTIALITY OF DATA AND PATIENT RECORDS ............................................................................... 22 
13 
PUBLICATIONS ......................................................................................................................... 23 
14 
RETENTION OF TRIAL DOCUMENTS ......................................................................................... 23 
15 
FUNDING AND INSURANCE ...................................................................................................... 23 

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PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Title: Development of advanced double intravenous vasopressor automated (ADIVA) system 
with improved hemodynamic trend control during spinal anaesthesia for Caesarean section 
 
 
Protocol Number: SHF/CTG061/2017 
 
 
Protocol Version/ Date: Version 1, 2 Aug 2018 
 
 
Sponsor Name: Singhealth Foundation Grant Clinical Trials Grant 
 
Declaration of Investigator 
 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct the 
described trial in compliance with all stipulations of the protocol, regulations and ICH E6 Guideline for 
Good Clinical Practice (GCP) 
 
  
 
 
Principal Investigator Name: Dr Singaraselvan Nagarajan 
                                                            
 
Principal Investigator Signature:  _______________________________________ 
                                                            
 
Date:  __________________________________________ 
                                                            
 
 
 
 
 
 
 

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1 
BACKGROUND AND RATIONALE 
 
Spinal anaesthesia has become more popular in recent years as the efficacy and safety of this 
anaesthetic technique is being established. Based a recent report, the total global volume of surgery 
procedure was estimated to be 312.9 million in year 2012, in which 7% are Caesarean sections (1, 
2). Over 95% of planned Caesarean sections in the United States used spinal anaesthesia (3). KK 
Hospital performs more than 6000 spinal anaesthesia procedure every year and 85% of Caesarean 
section is performed under regional anaesthesia with a majority being spinal anaesthesia. 
        
Spinal anaesthesia is a widely performed anaesthetic technique for surgery to the abdomen, pelvis 
and lower limbs. The advantages of this technique are reduction of airway complications associated 
with general anaesthesia, reduction in surgical bleeding and reduction in post-operative nausea and 
vomiting when compared with general anaesthesia (4, 5). However, this procedure is frequently 
associated with adverse hemodynamic changes and remains a common clinical problem. The most 
important severe side effects are hypotension (up to 33%) and bradycardia (up to 13%) in general 
surgical procedures (6, 7). During spinal anaesthesia for Caesarean section, maternal hypotension is 
even more common ranging from 70-90% incidence (8). 
 
Sympathetic autonomic blockade from spinal anaesthesia results in decreased perfusion to the 
cardiac, neurological and renal systems with potential organ dysfunction. The potential adverse 
effects resulted from maternal hypotension are maternal nausea, vomiting, cardiac dysfunction and 
foetal acidosis and hypoxia(9-11). Patients with autonomic dysfunction such as diabetes mellitus 
and elderly are at higher risk of hypotension and bradycardia that constitute national importance 
(12-14). 
 
Hypotension or bradycardia could be treated with manual bolus of vasopressors (15). Ephedrine 
increases the blood pressure and heart rate, whilst phenylephrine increases the blood pressure only. 
Volume expansion using fluids and during surgical bleeding, blood transfusion may be required. 
Severe and rapid progressing bradycardia and hypotension can become life threatening requiring 
rapid detection and treatment (16-17). The anaesthetists face the vigilant challenge to prevent mild 
variations in haemodynamic responses from spiralling into major hemodynamic compromise. 
 
Blood pressure fluctuations especially hypotension during spinal anaesthesia is currently detected 
using an intermittent blood pressure monitor cycling every 2 to 5 minutes and reactive 
administration of vasopressors upon detection of hypotension when the blood pressure reading is 
displayed intermittently (18).Additionally, the use of conventional non-invasive BP monitoring 
(based on the principle of oscillometry) is limited by the time required to inflate and subsequently 
to deflate the cuffs commonly applied to the arm. The lag period and lack of a ‘real-time’ 
measurement of BP may lead to a failure to react in a timely manner to the BP changes when they 
occur. During spinal anaesthesia for Caesarean delivery, haemodynamic instability could occur 
rapidly and suddenly – possibly leading to maternal and foetal complications (19).Stabilizing the 
hemodynamic status, being alert to downward trends in heart rate and blood pressure, and timely 
interventions to these changes are the critical steps in order to prevent catastrophic consequences 
such as cardiac collapse. 
 
Therefore, we developed a double intravenous vasopressor automated (DIVA) system in our 
institution to treat maternal hypotension during spinal anaesthesia for Caesarean delivery. We 
performed a randomised, double-blinded controlled trial which involved 226 healthy pregnant 
women who received spinal anaesthesia during elective Caesarean delivery. The results showed that 

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DIVA system dramatically decreased the incidence of maternal hypotension (39.3%, 46/117) 
compared to manual vasopressor bolus group (57.5%,65/113)(p=0.008). The DIVA system 
achieved less incidence of maternal hypotension and less wobble compared to Manual Vasopressor 
Bolus (MVB). However, the incidence of reactive hypertension, total vasopressor requirements, 
maternal nausea and vomiting, neonatal acid-base status and Apgar scores were similar. 
 
The DIVA system built in our centre renders a potentially cost-effective and efficacious way of 
providing individualised medicine. The algorithm has been improved during its development and 
shown to be superior to manual vasopressor bolus by the anaesthetist. . Although there was a 
significant reduction in the incidence of hypotension, the maternal and neonatal adverse effects 
were still not fully eliminated (20). A rapid bolus of vasopressor used in previous work was 
efficacious in treating hypotension, however this may lead to over treatment leading to higher risk 
of reactive hypertension. On the corollary, an infusion method may result in a slower but gentler 
response leading to lesser risk of reactive hypertension. 
 
We propose to improve the algorithm to achieve much stable haemodynamic outcomes. The 
analysis of 236 subjects in the most recent randomised controlled trial suggested that 
improvements can be made by refining the haemodynamic trend control and delivery of 
vasopressors looking at positive and negative trends in systolic blood pressure (21).For example, if 
a negative trend in systolic blood pressure is detected, a rapid bolus dose of vasopressor would be 
delivered to prevent further drop in blood pressure. On the other hand, with a positive trend in 
systolic blood pressure, an infusion method of vasopressor delivery may reduce the risk of reactive 
hypertension. Hypertensive response may be detrimental in high risk patients as this increases the 
risk of cardiac failure and stroke (9-11). This technology would lead to more stable haemodynamic 
profiles and improve patient outcomes by reducing maternal-foetal morbidity during caesarean 
section. 
 
In this proposed study we will develop a new algorithm for the advanced double intravenous 
vasopressor automated (ADIVA) system to control the blood pressure more rigorously by 
detecting the trend of blood pressure. Vasopressor dose will be adjusted as per the trend of the 
blood pressure recorded. We aim to improve on the stability of the systolic blood pressure by early 
proactive treatment of hypotension. This will be achieved by varying the amount of the 
vasopressor and varying the decision-making steps on whether a bolus or infusion delivery of 
vasopressor would be administered depending on presence of a negative or positive trend of 
systolic blood pressure, respectively. For example，when hypotension is detected and if the SBP 
trend is downward the pump will deliver the appropriate vasopressor as a bolus over 5 seconds 
(faster response, risk of reactive hypertension less as SBP trend is downward). On the other hand if 
hypotension is detected with an upward trend of SBP then the appropriate vasopressor dose is 
delivered as an infusion over 30 seconds (gentle and smooth response, slower response time 
accepted as SBP trend is upward). We believe this proactive management of hypotension based on 
the SBP trend and the speed of injection will improve on the stability of systolic blood pressure 
and decrease the incidence of reactive hypertension. 
 
1.1 General Introduction 
 
 
         We will set up ADIVA system by exporting BP and heart rate data measured by non-invasive 
blood pressure cardiac monitoring system to a computer that integrates the data every 10 
seconds. We propose to improve the algorithm so that a stable blood pressure can be maintained. 
We plan to achieve this by varying the amount of the vasopressor and determining whether a 

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bolus or infusion delivery of vasopressor would be administered depending on a negative or 
positive trend of systolic blood pressure respectively. Commands will be sent to activate either 
one of the pumps or neither based on the ADIVA algorithm described below. 
 
The investigators and delegated research personnel will assist to prepare the vasopressor drugs 
including phenylephrine and ephedrine in syringes and to place the medications on the 2 syringe 
pumps used in the study. 
 
A computer algorithm will deliver the vasopressors according to the set threshold of blood 
pressure and heart rate. 
 
1.2 Rationale and Justification for the Study 
 
 
Phenylephrine is a selective alpha 1 receptor agonist that results in vasoconstriction, increased 
systemic vascular resistance, bradycardia and may result in iatrogenic reactive hypertension in 
overdose which may be not be innocuous especially in high-risk patients (preeclampsia, cardiac 
disease). Ephedrine is an alpha and beta receptor agonist that results in vasoconstriction, 
increased systemic vascular resistance, increased heart rate and contractility. We propose to use 
two drugs (phenylephrine and ephedrine) to optimise the function of this highly novel closed-
loop feedback system to modulate the effects of iatrogenic reactive hypertension, bradycardia and 
reduction of uteroplacental blood flow due to high doses of phenylephrine alone, as well as 
controlled fluid administration to address any deficiencies in intravascular volume. Furthermore, 
our target-controlled system could identify patients who are at risk of developing hypotension 
and hence, need more vasopressors to maintain normal hemodynamic status. We would also be 
able to identify (and appropriately treat) patients who may develop bradycardia by the use of 
ephedrine rather than phenylephrine based on heart rate criteria. The presence of such an 
innovation to provide an individualised approach based on a closed loop feedback system to 
maintain hemodynamic stability will assist anaesthetists in the perioperative and intensive care 
settings. 
 
1.2.1 Rationale for the Study Purpose 
 
The DIVA system built in our centre renders a potentially cost-effective and efficacious way of 
providing individualised medicine. The algorithm has been improved during its development 
and shown to be superior to manual vasopressor bolus by the anaesthetist. . Although there was 
a significant reduction in the incidence of hypotension, the maternal and neonatal adverse 
effects were still not fully eliminated (20). A rapid bolus of vasopressor used in previous work 
was efficacious in treating hypotension, however this may lead to over treatment leading to 
higher risk of reactive hypertension. On the corollary, an infusion method may result in a slower 
but gentler response leading to lesser risk of reactive hypertension. 
 
We propose to improve the algorithm to improve the stability of haemodynamic outcomes. The 
analysis of 236 subjects in the most recent randomised controlled trial suggested that 
improvements can be made by refining the haemodynamic trend control and delivery of 
vasopressors looking at positive and negative trends in systolic blood pressure (21). For 
example, if a negative trend in systolic blood pressure is detected, a rapid bolus dose of 
vasopressor would be delivered to prevent further drop in blood pressure. On the other hand, 
with a positive trend in systolic blood pressure, an infusion method of vasopressor delivery may 
reduce the risk of reactive hypertension. Hypertensive response may be detrimental in high risk 

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patients as this increases the risk of cardiac failure and stroke (9-11). This technology would lead 
to more stable haemodynamic profiles and improve patient outcomes by reducing maternal-fetal 
morbidity during caesarean section. 
  
In this proposed study we will develop an improved algorithm for the advanced double 
intravenous vasopressor automated (ADIVA) system to control the blood pressure more 
rigorously by detecting the trend of blood pressure. Vasopressor dose will be adjusted as per the 
trend of the blood pressure recorded. We aim to improve on the stability of the systolic blood 
pressure by early proactive treatment of hypotension. This will be achieved by varying the 
amount of the vasopressor and varying the decision-making steps on whether a bolus or 
infusion delivery of vasopressor would be administered depending on presence of a negative or 
positive trend of systolic blood pressure, respectively. For example when hypotension is 
detected and if the SBP trend is downward the pump will deliver the appropriate vasopressor as 
a bolus over 5 seconds (faster response, risk of reactive hypertension less as SBP trend is 
downward). On the other hand if hypotension is detected with an upward trend of SBP then the 
appropriate vasopressor dose is delivered as an infusion over 30 seconds (gentle and smooth 
response, slower response time accepted as SBP trend is upward). We believe this proactive 
management of hypotension based on the SBP trend and the speed of injection will improve on 
the stability of systolic blood pressure and decrease the incidence of reactive hypertension.        
     
1.2.2 Rationale for Doses Selected 
 
Our new ADIVA algorithm is significantly different from DIVA algorism. The DIVA 
algorithm used a two-step decision process for vasopressor administration based on the 
percentage drop of systolic blood pressure (SBP) with two different dose regimen for the 
vasopressors (Phenylephrine 50mcg or 25 mcg (with heart rate > 60), ephedrine 4 mg or 2mg 
(with heart rate <60) when SBP is below 90% or between 90-100% respectively.  
 
In the ADIVA algorithm in addition to the percentage drop in SBP from baseline, the SBP 
trend plays a key role in the way the vasopressor is being administered. Hypotension in the 
presence of up trending SBP is treated by administering the vasopressor as an infusion over 30 
seconds. Hypotension in the presence of down trending SBP is treated by administering the 
vasopressor as a bolus given over 5 seconds. The dose of vasopressor administered is graded in 
response to the degree of hypotension (phenylephrine 25 mcg, 25 mcg, 50 mcg or 75 mcg (with 
heart rate >60) or ephedrine 2 mg, 2 mg, 4mg or 6 mg (with heart rate < 60) when SBP is 
100%-110%, 90%-100%, 80-90% or <90% respectively). 
 
During hypotension with a down trending SBP, a rapid bolus dose of vasopressor would 
prevent further drop in blood pressure. On the other hand, hypotension with an up trending 
SBP treated with vasopressor infusion may prevent the risk of reactive hypertension. 
 
We believe this proactive management of hypotension based on the SBP trend and the speed of 
injection will improve on the stability of systolic blood pressure and decrease the incidence of 
reactive hypertension.  
 
1.2.3 Rationale for Study Population 
 
We are investigating the improved algorithm to manage blood pressure during spinal  
anaesthesia for Caesarean delivery. Hence, our study population must be the parturients who 
undergo spinal anaesthesia for Caesarean delivery.  

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This study will be conducted with the approval of the Centralised Institutional Review Board 
(CIRB) from SingHealth, Health Sciences Authority and clinical trials registration. Informed 
written consent will be obtained from every patient who participated in the study. The healthy 
women with singleton pregnancy scheduled for elective Caesarean section at term and who 
requested for spinal anaesthesia will be recruited.  
 
The inclusion criteria are:  
• 
The indication for an elective Caesarean section. 
• 
The use of spinal anaesthesia for Caesarean section. 
•           Anthropometric profile within the following range: age 21-45 years old, weight 40-90 kg  
and height of 145-170 cm. 
 
The exclusion criteria are: 
• 
The presence of at least one medical condition e.g. hypertension, diabetes mellitus and  
other cardiovascular disease, which is not well controlled. 
• 
Contraindication to spinal anaesthesia and/or allergy to opioids. 
 
1.2.4 Rationale for Study Design 
 
There are two phases in this study.  
 
Phase 1 is a pilot study to recruit 60 healthy pregnant women to investigate the efficacy and 
safety of the ADIVA algorithm. 
 
Phase 2 is a double-blinded, randomized (1:1 allocation ratio) trial design. This is to investigate 
the use of ADIVA system in comparison to the existing DIVA system. 
The experimental group will be using the ADIVA system and the comparator control group will 
be using the DIVA system. There is no placebo control in this trial design. 
 
Women will be randomly assigned to the experimental and control groups in a 1:1 allocation 
ratio based on a computer-generated code that will be prepared at a remote site and sealed in 
opaque, sequentially-numbered envelopes by the ‘unblinded’ CRC. The women will be allocated 
to one of the two groups:  
(a) Group ADIVA (experimental) will receive treatment as per the new advanced algorithm;  
(b) Group DIVA (control) will be managed as per the DIVA algorithm 
 
Both the patients and the anaesthetist responsible for collecting and analysing the study 
parameters are ‘blinded’ to the allocation. 
 
2 
HYPOTHESIS AND OBJECTIVES 
 
 
2.1 Hypothesis 
 
          Refer to section 2.2. 
           
2.2 Primary Objective 
         Primary Objective  

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To determine the incidence of maternal hypotension between the new ADIVA system and the 
DIVA system in term women with singleton pregnancy who undergo elective caesarean section 
under standardized spinal anaesthesia. 
         
 Primary Hypothesis 
The incidence^ of maternal hypotension* in the ADIVA system will be less than or 
equal to 18% compared to the DIVA system. 
 
^Incidence of maternal hypotension of DIVA system: 39%; derived from previous studies by the research team. 
 
*Hypotension is defined as any reading of systolic blood pressure below 80% of the baseline systolic blood pressure. 
Blood pressure monitoring is done using continuous non-invasive blood pressure monitoring device (continuous 
non-invasive arterial pressure (CNAP) cardiac monitoring. 
 
2.3 Secondary Objectives 
 
Secondary Objectives 
1. To determine the incidence of reactive hypertension, nausea and vomiting, amount of 
vasopressor use and foetal outcomes (cord pH, APGAR scores) of the ADIVA system. 
 
2. To determine the cardiac output (reflection of cardiac function) and systemic vascular 
resistance (resistance to blood flow in the circulation) using cardiac monitoring of ADIVA 
system. 
 
 
Secondary Hypotheses 
 
1) The incidence of reactive hypertension using the ADVIA system will be lesser than 
DIVA system. 
2) The incidence of nausea and vomiting using the ADIVA system will be less than 
DIVA system. 
3) The amount of vasopressor use using the ADIVA system will be similar to the 
DIVA system. 
4) The cord pH and APGAR scores (foetal outcomes) using the ADVIA system will 
be similar to the DIVA system. 
5) The cardiac output and systemic vascular resistance using cardiac monitoring of 
ADIVA system will be similar to the DIVA system. 
 
2.4 Potential Risks and Benefits:  
 
2.4.1 Potential Risks 
There is no additional risk to the patient or her baby by participating in this study. If there are 
any side effects during the spinal anaesthesia, this would be expeditiously and effectively treated. 
Rare side effects include respiratory difficulty, nerve injury and post dural puncture headache 
that are not increased by this study, and are risks associated with spinal anaesthesia as listed in 
anaesthesia consent form. The drugs (phenylephrine and ephedrine) and the dosage used are the 
same as standard of care, so there is no additional risk to the patients. However, there may have 
changes during surgery that may lead to low blood pressure or high blood pressure from the 
administration of medications. 
 
The attending anaesthetist will treat these side effects accordingly. The proposed double-

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vasopressor system does not pose additional clinical risks when compared to other commercial 
syringe driver pumps. Not only does the pump contain the necessary safety checks and controls, 
it includes an additional safety feature which prevents infusion from exceeding an hourly dosage 
limit set by the investigators. There is a rare chance that the ADIVA system may malfunction. If 
this occurs, the blood pressure control will be taken. 
 
2.4.2 Potential Benefits 
Our hypothesis is that the proposed ADIVA system would further stable patients’ 
haemodynamic outcomes and reduce maternal-fetal adverse events during caesarean section, 
which subsequently provide better maternal satisfaction. This will translate into a more 
comfortable delivery experience for parturients with greater patient safety in anaesthesia. In 
addition, preliminary data has shown the need to develop this technology so as reduce 
perioperative haemodynamic instability during anaesthesia and prevent cardiac and neurological 
adverse events. By participating in this study, patients may help to contribute to the 
development roadmap by allowing us to test on the algorithm to further improve 
haemodynamic stability and reduce maternal-fetal morbidity during caesarean section as well as 
extend the application of this technology to other anaesthetic settings. 
 
3 
STUDY POPULATION 
 
3.1       List The Number and Nature of Subjects to be enrolled.  
Phase 1: 70   healthy pregnant women 
Phase 2: 230 healthy pregnant women  
All patients to be recruited will be from KK Women’s and Children’s Hospital. 
 
3.2      Criteria for Recruitment and Recruitment Process 
 
This study will be advertised on study brochures.  Patients who are undergoing elective 
caesarean surgery will receive study information either at pre-anaesthetic clinic or upon 
admission for surgery if they have not attended the pre-anaesthetic clinic. They will be screened 
for eligibility using the inclusion and exclusion criteria. If eligible for recruitment, the patients 
will be approached by the investigators for recruitment. Recruitment will be performed in the 
preanaesthetic clinic or on the same day of surgery if they have not attended pre-anaesthetic 
clinic. Research personnel will conduct all discussions about the study and answer any questions 
in a private manner in the consultation rooms. They will be counselled regarding the alternatives 
and given an opportunity to ask questions and clarify doubts. Ample time will be given to the 
potential patients for consent taking. Consent will be obtained in writing upon their willingness 
and agreement to participate in the study. With the activation of HBRA, informed consent will 
be obtained in the presence of a prescribed witness. 
 
3.3      Inclusion Criteria 
 
The inclusion criteria are:  
 
Anthropometric profile within the following range: age 21-50 years old, weight 40-90 kg 
and height of 145-170 cm. 
 
Healthy adult (American Society of Anesthesiologists physical status 1 and 2) parturients; 
 
With singleton full-term pregnancy; 
 
The indication for an elective cesarean delivery; 

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 
The use of spinal anaesthesia for cesarean delivery; 
 
3.4     Exclusion Criteria 
 
The exclusion criteria are: 
 
Obstetric (e.g. pre-eclampsia, premature rupture of amniotic membranes for more than 48 
hours, gestational diabetes on insulin, pregnancy-induced hypertension on medication) and 
uncontrolled medical(e.g. cardiac disease) complications; 
 
Contraindication to spinal anaesthesia and/or allergy to opioids. 
 
3.5     Subject Replacement 
           No subject replacement will be performed. 
 
4      STUDY DESIGN 
 
           There are two phases involved in this study.  
 
Phase 1 is an open-labelled pilot study to assess the efficacy and safety of the ADIVA 
algorithm.  
 
Phase 2 is a double-blinded, randomized (1:1 allocation ratio) trial design. The experimental 
group will be using the ADIVA system and the comparator control group will be using the 
DIVA system. 
 
There is no placebo control in this trial design. Women will be randomly assigned to the 
experimental and control groups in a 1:1 allocation ratio based on a computer-generated code 
that will be prepared at a remote site and sealed in opaque, sequentially-numbered envelopes by 
the ‘unblinded’ CRC. The women will be allocated to one of the two groups: 
 
a) Group ADIVA (experimental) will receive treatment as per the new advanced algorithm.  
(Refer to Figure 1, Schematic diagram of the algorithm used in the ADIVA system).  
Our new ADIVA algorithm is significantly different from DIVA algorism.  
 
The DIVA algorithm used a two-step decision process for vasopressor administration 
based on the percentage drop of systolic blood pressure (SBP) with two different dose 
regimen for the vasopressors (Phenylephrine 50mcg or 25 mcg (with heart rate > 60), 
ephedrine 4 mg or 2 mg (with heart rate <60) when SBP is below 90% or between 90-
100% respectively)  
 
In the ADIVA algorithm in addition to the percentage drop in SBP from baseline, the SBP 
trend plays a key role in the way the vasopressor is being administered. Hypotension in the 
presence of up trending SBP is treated by administering the vasopressor as an infusion over 
30 seconds. Hypotension in the presence of down trending SBP is treated by administering 
the vasopressor as a bolus given over 5 seconds. The dose of vasopressor administered is 
graded in response to the degree of hypotension (phenylephrine 25 mcg, 25 mcg, 50 mcg 
or 75 mcg (with heart rate >60) or ephedrine 2 mg, 2 mg, 4mg or 6 mg (with heart rate < 
60) when SBP is 100%-110%, 90%-100%, 80-90% or <90% respectively). 
 
 

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(inf – Infusion; bol – Bolus; P – Phenylephrine; E – Ephedrine) 
Figure 1: Schematic diagram of the algorithm used in the ADIVA system 
 
 
b) Group DIVA (control) will be managed as per the DIVA algorithm. (Please refer to figure 
2. Schematic diagram of the algorithm used in the DIVA system).The DIVA system will 
infuse vasopressors of phenylephrine of 25mcg (SBP 90-100% of baseline and HR 
≥60/min) or ephedrine 2 mg (SBP 90-100% of baseline and HR <60/min) every 30 
seconds based on Nexfin cardiac monitoring BP measurements and if the blood pressure is 
lower, phenylephrine of 50mcg (SBP <90% of baseline and HR >60/min) or ephedrine 
4mg (SBP <90% of baseline and HR <60/min) every 30 seconds based on Nexfin cardiac 
monitoring BP measurements.  
 
Rescue phenylephrine 100mcg boluses, ephedrine 3mg boluses and atropine 0.6mg boluses 
will be made available for both groups if systolic BP remains less than 70% baseline values 
or HR remains <60/min for more than 3 minutes by the clinician. 
 

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Figure 2: Schematic diagram of the algorithm used in the DIVA system 
 
 
 
4.1 
Randomisation and Blinding 
            Computer generated code are preprared preoperatively in a 1:1 ratio by the statistician from  
Duke-NUS Medical School using a computer generated random number sequence and will be 
allocated to one of two groups using sealed opaque envelopes.  
 
Women will be randomly assigned to the experimental and control groups in a 1:1 allocation 
ratio based on a computer-generated code that will be prepared at a remote site and sealed in 
opaque, sequentially-numbered envelopes by the ‘unblinded’ CRC. The women will be allocated 
to one of the two groups: 
 
(a) Group ADIVA (experimental) will receive treatment as per the new advanced algorithm; 
(b) Group DIVA (control) will be managed as per the DIVA algorithm. 
 
Unblinded team: The designated clinical research coordinators will perform randomization after 
consent taken.  System will be set up by them according to the treatment group allocated. The 
monitor screen will not show the treatment group. 
 
Blinded team: Both the patients and the anaesthetist who are responsible for collecting and 
analysing the study parameters are ‘blinded’ to the allocation.   
 
Study drug preparation will be performed by any delegated study members in view that no 
unblinding issue is involved. 
 
4.2 
Contraception and Pregnancy Testing 
  Not applicable. 

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4.3 
Study Visits and Procedures 
 
4.3.1 Screening Visits and Procedures 
 
            Eligible subjects will be screened for their eligibility and recruited at the antenatal pre-admission 
caesarean section clinics or in the same day admission ward. The study will be terminated when 
the patient is discharged from the recovery room after surgery.  
 
The study is conducted in the operating theatre room where the subject has her Caesarean 
section under spinal anaesthesia. 
 
Subjects may withdraw voluntarily from participation in the study at any time. Subjects may also 
withdraw voluntarily from receiving the study intervention for any reason. If voluntary 
withdrawal occurs, the subject will be given spinal anaesthesia for Caesarean section and 
postoperative analgesia as per routine hospital practice 
 
Patients who have consented to participate in the study will have their case notes/medical 
records reviewed to confirm their eligibility for the study. The relevant data from the case notes 
will be recorded in the data collection form.  
 
4.3.2 Study Visits and Procedures 
 
Visit 1 (Before surgery) 
- Patient recruitment before the surgery 
- Randomization (only for Phase 2 patients) 
- Baseline Demographic data collection 
- Setting up spinal anaesthesia and connection to ADIVA system 
 
 
Medical Procedures during this visit are the following:  
  
1) Intravenous access before surgery will be established using an 18G cannula.  
2) Continuous non-invasive blood pressure and cardiac output system have finger cuffs will be 
placed on the right or left second or middle finger. The average value of 3 readings after the 
patient has rested for 15 minutes will be taken as the baseline systolic BP value. Every 
patient will receive a spinal anaesthesia in the sitting position. After ensuring a free flow of 
cerebrospinal fluid (CSF), 2.3mls of 0.5% heavy bupivacaine 15 mg fentanyl and 100 mg of 
morphine will be injected intrathecally over 15 sec with the orifice of the spinal needle 
facing in the cephalad direction which is the routine dose of spinal medications. 
3) Each patient will receive IV 1000ml of Hartmann’s for coloading fast. Antiemetics 
(ondansetron 4 mg and dexamethasone 4mg) will be routinely given after the delivery of the 
foetus.  
 
 
Data collection  
The following data regarding the patients will be collected: ethnic group, age, weight, height, 
gestational age. In addition, the following clinical data of the patients will be recorded: 
Systolic and diastolic blood pressure; Heart rate; Cardiac output and systemic vascular 
resistance; Total amount of vasopressors (ephedrine and phenylephrine) used. 
 
The presence of the following data will be recorded by the research coordinator who is not 

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involved in the clinical care of the patient at 5 min intervals: 
Motor block (modified Bromage scale: 0 = no block, 1 = unable to flex either hip joint but 
able to move knee and ankle joints, 2 = unable to move hip and knee of either limb but able to 
move either ankle, 3= unable to move hip, knee or ankle joint of either lower limb); 
Sensory block level; Presence of shivering (0 = no, 1 = yes), nausea (0 = no, 1 = yes), vomiting 
(0 = no, 1 = yes). 
 
Visit 2 (After surgery) 
Data collection: 
 
Neonatal APGAR scores at 0 and 5 minutes; 
 
Neonatal arterial and venous cord pH; 
 
Maternal satisfaction and intraoperative pain scores with the anaesthesia technique at the 
end of the surgery (0-100 numerical rating scale); 
 
Adverse events. 
            
Please refer to Appendix 1 for Study Schedule, appendix 2 for data collection form used in the 
study. 
 
4.3.3 Final Study Visit: 
 
The study will be terminated after discharge from the recovery room. No further follow-up will   
be required. 
 
4.3.4 Post Study Follow up and Procedures 
 
No post study follow up and procedures will be performed. 
 
4.4 
Discontinuation/Withdrawal 
 
4.4.1 Discontinuation Criteria 
 
The stopping criteria for the research study will be based on safety criteria. The review of 
serious adverse effects will be performed. 
 
4.4.2 Discontinuation Visit and Procedures 
 
Hourly postoperative monitoring and routine follow up of all patients for 24 hours is carried 
out in our current practice following any regional anaesthetic for caesarean section. This will 
also be performed for those patients who withdraw from the study and undergo caesarean 
section under regional anaesthesia. 
 

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4.5 
Discontinuation/Withdrawal 
 
4.5.1 Discontinuation Criteria 
 
The stopping criteria for the research study will be based on safety criteria. The review of 
serious adverse effects will be performed. 
 
4.5.2 Discontinuation Visit and Procedures 
 
Hourly postoperative monitoring and routine follow up of all patients for 24 hours is carried 
out in our current practice following any regional anaesthetic for caesarean section. This will 
also be performed for those patients who withdraw from the study and undergo caesarean 
section under regional anaesthesia. 
 
5 
TRIAL MATERIALS 
 
5.1 
Trial Product (s) 
 
Phenylephrine is a selective alpha 1 receptor agonist that results in vasoconstriction, increased 
systemic vascular resistance, bradycardia and may result in iatrogenic reactive hypertension in 
overdose which may be not be innocuous especially in high-risk patients (preeclampsia, cardiac 
disease). Ephedrine is an alpha and beta receptor agonist that results in vasoconstriction, 
increased systemic vascular resistance, increased heart rate and contractility. We propose to use 
two drugs (phenylephrine and ephedrine) to optimise the function of this highly novel closed-
loop feedback system to modulate the effects of iatrogenic reactive hypertension, bradycardia 
and reduction of uteroplacental blood flow due to high doses of phenylephrine alone, as well as 
controlled fluid administration to addressany deficiencies in intravascular volume. Furthermore, 
our target-controlled DIVA & ADIVA system could identify patients who are at risk of 
developing hypotension and hence, need more vasopressors to maintain normal hemodynamic 
status. We would also be able to identify (and appropriately treat) patients who may develop 
bradycardia by the use of ephedrine rather than phenylephrine based on heart rate criteria. The 
presence of such an innovation to provide an individualised approach based on a closed loop 
feedback system to maintain hemodynamic stability will assist anaesthetists in the perioperative 
and intensive care settings.  
 
 
5.2 
Storage and Drug Accountability 
 
           Phenylephrine is available as a 1mg/10mL ampoule. It is stored at room temperature. 
 
Ephedrine is available as a 1ml 30mg ampoule. Ephedrine will be diluted to 8mg/ml with 
normal saline. It is stored at room temperature. 
 
6 
TREATMENT 
6.1 
Rationale for Selection of Dose 
 
Doses selected are based on previous studies done by our research team. Previous studies have  
shown equivalent vasopressor activity of 100mcg of phenylephrine and 8mg ephedrine. The 
vasopressors are administered in the intravenous route. 

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6.2 
Study Drug Formulations 
 
Phenylephrine is available as a 1 mg/10 ml ampoule.  2 vials of Phenylephrine will be used to 
prepare into 50 mls syringe (total volume 15 ml). 
 
Ephedrine is available as a 1ml 30mg ampoule. It is stored at room temperature.  2 vials of 
ephedrine 30mg/ml (1 ml each) will be diluted to 8mg/ml with 5.5 ml of normal saline (total 
volume 7.5mls). 2x ephedrine 30mg/ml (1mls each) + 5.5 mls N/S into 10ml syringe (total volume 7.5mls) 
 
6.3 
Study Drug Administration 
 
Drug administration is through the DIVA or ADIVA algorithm as shown in Section 4 Figure 
1&2. 
6.4 
Specific Restrictions / Requirements  
 
Not applicable. 
 
6.5 
Blinding 
 
Patients will be randomised preoperatively in a 1:1 ratio by the statistician from Duke-NUS 
School using a computer generated random number sequence and will be allocated to one of 
two groups using sealed opaque envelopes.  
 
The patients and anaesthetists who are involved in data collection are blinded in this study. The 
designated research coordinators in this study are in the unblinded group and will perform 
randomization as well as pump setting up.  
 
Drugs preparation will be performed by delegated study team members. 
 
 
6.6 
Concomitant therapy 
 
Not Applicable.  
7 
SAFETY MEASUREMENTS 
7.1 
Definitions 
            An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation  
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. 
 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at any dose: 
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing hospitalisation 
 results in persistent or significant disability/incapacity or 
 is a congenital anomaly/birth defect 

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 is a medical event that may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
Phenylephrine and ephedrine are indirect acting vasopressors. Possible side effects of 
phenylephrine and ephedrine (based on previous studies) include: 
 
Tachyphylaxis 
 
Reactive hypertension 
 
Patients will be monitored for these side effects and given symptomatic relief accordingly by the 
principal investigator or co-investigator. In the unlikely situation that these symptoms result in 
prolonged hospital stay, this will be reported to the HSA and CIRB. 
 
In this study, the following adverse event will be collected and reported:  
 
Hypotention (less than 70% of baseline for >5 mins) 
 
Persistent maternal severe bradycardia (less than 50 beats per minute for > 5 mins, before 
delivery  
 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at any dose: 
 results in or contributes to death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing hospitalisation 
 results in or contributes to persistent or significant disability/incapacity or 
 results in or contributes to a congenital anomaly/birth defect 
 results in such other events as may be prescribed  
 
7.2 
Collecting, Recording and Reporting of Adverse Events and Serious Adverse 
Events to CIRB  
 
Reporting of adverse events involves the PI submitting to the approving CIRB the completed 
SAE Reporting Form within the stipulated timeframe. PI is responsible for informing the 
institution representative (local SAE resulting in death), sponsor or regulatory bodies as 
required and appropriate. 
 
Reporting timeline to CIRB:  
 
 SAE that result in death, regardless of causality, should be reported immediately - within 
24 hours of the PI becoming aware of the event.  
 Local life-threatening (unexpected/ expected) SAE should be reported no later than 7 
calendar days after the Investigator is aware of the event, followed by a complete report 
within 8 additional calendar days. 
 Local unexpected SAE that are related events, but not life-threatening, should be 
reported no later than 15 calendar days after the investigator is aware of the event. 
 An increase in the rate of occurrence of local expected SAE, which is judged to be 
clinically important, should be reported within 15 calendar days after the PI is aware of 
the event.  
 Local expected SAE should be reported annually (together with Study Status Report for 
annual review). 

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 Local unexpected and unlikely related SAE that are not life-threatening should also be 
reported annually (together with Study Status Report for annual review). 
 Local unexpected AE that are related events should be reported at least annually 
(together with Study Status Report for annual review). 
 Non-local 
unexpected 
SAE 
that 
are 
fatal 
or 
life 
threatening 
and 
definitely/probably/possibly related should be reported not later than 30 calendar days 
after the PI is aware of the event. 
 
7.3 
Collecting, Recording and Reporting of Serious Adverse Events (SAEs) to the 
Health Science Authority (HSA) 
 
All SAEs that are unexpected and related to the study drug will be reported to HSA. All SAEs 
will be reported to HSA. Please refer to the HSA website for more information on Safety 
Reporting Requirements for Clinical Trials.  
 
The investigator is responsible for informing HSA no later than 15 calendar days after first 
knowledge that the case qualifies for expedited reporting. Follow-up information will be actively 
sought and submitted as it becomes available. For fatal or life-threatening cases, HSA will be 
notified as soon as possible but no later than 7 calendar days after first knowledge that a case 
qualifies, followed by a complete report within 8 additional calendar days. 
 
 
7.4 
Safety Monitoring Plan 
 
The plan for adverse effect monitoring, severe adverse effect monitoring and unforeseen 
reactions would include reporting of adverse effects to the Health Sciences Authority and 
Central Institutional Review Board. 
 
Safety data is monitored at all times by the principal investigator, co-investigators and attending 
anaesthetists in the operating theatres. The study drug would only be available in the operating 
theatres. The principal investigator and co-investigators would institute medical treatment, e.g. 
anti-emetics for nausea and vomiting, intravenous fluid loading and vasopressors for 
hypotension, analgesics for pain during caesarean delivery.  
 
There is no interim analysis. Approval from the Health Sciences Authority would be sought 
before the trial commences. 
 
7.5 
Complaint Handling  
 
Any complaints arising from the conduct of the study will be reviewed and the patient 
interviewed by the principal investigator. Any serious or potentially litigious complaints will be 
reported to the Health Sciences Authority and Institutional Review Board. 
 
The data will be kept locked by the principal investigator and by the use of computer security of 
Singhealth. The data will be accessible only the investigators and for analysis purposes only. The 
data and computer will be under locked in the office of the principal investigator. 
 

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8 
DATA ANALYSIS 
8.1 
Data Quality Assurance 
 
Data obtained from this research that has been keyed into the appropriate computer software 
programme will be counter-checked by a second investigator to ensure that it is accurate, 
complete and reliable. 
 
8.2 
Data Entry and Storage 
 
The subjects would be de-identified and only the study number would be communicated 
through in electronic softcopy format. Data entry will be in softcopy format and The soft copy 
of research data will be stored in a password protected PC. Hard copies of data collection forms 
are kept by the Principal Investigator under lock and key. The data is accessible only by 
Investigators for analysis purposes only. The research data will be kept under lock and key and 
using computer security of Singhealth. The data will be destroyed after keeping for 6 years upon 
completion of the study. 
 
9 
SAMPLE SIZE AND STATISTICAL METHODS 
 
9.1 
Determination of Sample Size  
 
Our primary outcome of this study is the incidence of hypotension. A sample size of 204 
(102 X 2) is required to show that the incidence of maternal hypotension in the experimental 
group 18% and the control group 39%, based on the following assumptions: proportion of 
hypotension in DIVA group =0.39, proportion of hypotension in ADIVA group = 0.18, 1:1 
allocation ratio, α = 0.05 and power = 80%. Sample size calculations accounted for a 
conservative 20% dropout rate due to spinal anaesthesia placement failure. Two hundred and 
four patients are required to adequately power the study. 
 
9.2 
Statistical and Analytical Plans 
a. General Considerations 
b. Safety Analyses 
 
c. Interim Analyses 
 
d. Describe the types of statistical interim analyses, including their timing. 
 
The primary specific aims will be addressed by estimating the incidence of hypotension in the  
experimental and control groups, together with their corresponding 95% confidence interval 
CI). A univariate analyses will be performed with possible logistic regression modelling to adjust 
for unbalanced potential baseline confounders. 
 
Our secondary outcomes include the incidence of reactive hypertension, nausea or vomiting, the 
amount of vasopressor, cardiac output and systemic vascular, umbilical cord blood pH and 
APGAR scores with anaesthesia technique. Student’s t-test will be used to compare the data 
that are normally distributed. Otherwise, the Mann Whitney test will be used. For nominal data 
and proportions, the c2 test with Yates correction when appropriate, will be used. 
 

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We will also assess the reliability of ADIVA system by calculating the percentage performance 
error (the percentage difference between measured BP and baseline BP), median performance 
error (median of percentage performance error, a measure of bias), median absolute  
performance error (median of the absolute values of performance error, a measure of 
inaccuracy), wobble (median of the absolute difference between percentage performance error 
and median performance error at every time point) and divergence (measures the trend of 
changes in percentage performance error) (21). 
 
10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
The investigator(s)/institution(s) will permit study-related monitoring, audits and/or IRB review 
and regulatory inspection(s), providing direct access to source data/document. 
 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
Data is extracted from data collection forms and random audits will be performed to make sure 
it is authentic, accurate and complete. 
 
12 
ETHICAL CONSIDERATIONS 
 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with the Good Clinical Practice and the 
applicable regulatory requirements. 
 
This final study protocol, including the final version of the Patient Information and Informed 
Consent Form, must be approved in writing by the Centralised Institutional Review Board 
(CIRB) and regulatory approval from Health Sciences Authority (HSA), prior to enrolment of 
any patient into the study. 
 
The principle investigator is responsible for informing the CIRB and HSA of any amendments 
to the protocol or other study-related documents, as per local requirement. 
 
12.1 Informed Consent 
 
The informed consent process will be conducted by a trained study team member as shown in      
the delegation log.  The informed consent process will be conducted in compliance with ICH-
GCP. 
 
12.2 Confidentiality of Data and Patient Records 
 
The subjects would be de-identified and only the study number would be communicated 
through in electronic softcopy format. Data entry will be in softcopy format and the data will be 
kept under lock and key using the computer security of Singhealth. The data will be destroyed 
after keeping for up to 6-years after completion of the study. 
 

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13 
PUBLICATIONS 
Study findings will be published in indexed journals (at least two publications expected). 
 
 
14 
RETENTION OF TRIAL DOCUMENTS 
 
Records for all participants, patient informed consent forms, IRB records and other regulatory 
documentation will be retained by the PI and locked securely in a storage cupboard. The records 
will be accessible for inspection and copying by authorized authorities.  
 
(1) The holder of a certificate shall keep adequate clinical records of each subject for the 
duration of the clinical trial. 
 
(2) The holder of a certificate shall ensure that such records are — 
(a) kept up to date at all times; 
(b) available at all times for inspection by the licensing authority or any person authorised 
by him in that behalf;  
(c) kept at least for whichever of the following periods expires later: 
(i) until there are no pending or contemplated marketing applications of the test 
material in Singapore; 
(ii) 2 years after the last approval of a marketing application for the test material 
in Singapore; 
(iii) where the clinical trial is discontinued, 2 years after the licensing authority 
has been informed of the discontinuation of the clinical trial under 
regulation 9; 
(iv) 6 years after the completion of the clinical trial; or 
(v) such other period as the licensing authority may direct. 
 
(3) The holder of a certificate shall maintain a record containing the names and such other 
particulars of every person assisting or participating in a clinical trial. 
 
(4) In this regulation, “marketing application” means an application for a product licence under 
the Act in respect of the test material. 
 
 
 
15      FUNDING and INSURANCE 
 
 
Singhealth Foundation Grant Clinical Trials Grant has been awarded to support this study.  
Study is covered by the National Clinical Trial Insurance. 
 

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List of Attachments 
 
Appendix 1 
Study Schedule 
 
Appendix 2 
 
Data Collection Form  
 
Appendix 3      List of References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1. Study Schedule (Version 1, dated 23 Feb 2018) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 2: Data Collection Form (Version 1, dated 28 Feb 2018) 
 

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Appendix 3. List of References  
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volume of surgery in 2012. Bull World Health Organ. 2016 Mar 1;94(3):201-209F.  
2.      Weiser TG, Haynes AB, Molina G, Lipsitz SR, Esquivel MM, Uribe-Leitz T, Fu R, Azad T, Chao TE, Berry WR, Gawande AA. Estimate of the global volume of 
surgery in 2012: an assessment supporting improved health outcomes. Lancet. 2015 Apr 27;385 Suppl 2:S11.  
3.      Bucklin BA, Hawkins JL, Anderson JR, Ullrich FA. Obstetric anesthesia workforce survey: twenty-year update. Anesthesiology. 2005 Sep;103(3):645-53.  
4.      Attari MA, Mirhosseini SA, Honarmand A, Safavi MR. Spinal Anesthesia Versus General Anesthesia for Elective Lumbar Spine Surgery: A Randomized Clinical 
Trial. J Res Med Sci 2011;16:524-529. 
5.      Goeller JK, Bhalla T, Tobias JD. Combined Use of Neuraxial and General Anesthesia During Major Abdominal Procedures in Neonates and Infants. Paediatr 
Anaesth 2014;24:553-560. 
6.      Carpenter RL, Caplan RA, Brown DL, Stephenson C, Wu R: Incidence and risk factors for side effects of spinal anesthesia. ANESTHESIOLOGY 1992; 76:906–16 
7.      Arndt JO, Bomer W, Krauth J, Marquardt B: Incidence and time course of cardiovascular side effects during spinal anesthesia after prophylactic administration 
of intravenous fluids or vasoconstrictors. Anesth Analg 1998; 87:347–54 
8.      Roofthooft E, Van de Velde M. Low-dose spinal anaesthesia for Caesarean section to prevent spinal-induced hypotension. Curr Opin Anaesthesiol. 2008 
Jun;21(3):259-62.  
9.      Smiley RM, Blouin JL, Negron M, Landau R. beta2-adrenoceptor genotype affects vasopressor requirements during spinal anesthesia for cesarean delivery. 
Anesthesiology. 2006 Apr;104(4):644-50. 
10.    Greiss FC Jr. Pressure-flow relationship in the gravid uterine vascular bed. American Journal of Obstetrics and Gynecology 1966; 96: 41–7. 
11.    Hawthorne, L. & Lyons G.Cardiac arrest complicating spinal anaesthesia for caesarean section. Int J Obstet Anesth, 1997. 6(2):126-9. 
12.    Crites J, Ramanathan J. Acute hypoglycemia following combined spinal-epidural anesthesia (CSE) in a parturient with diabetes mellitus. Anesthesiology. 2000 
Aug;93(2):591-2. 
13.    Buggy DJ, Power CK, Meeke R, O'Callaghan S, Moran C, O'Brien GT. Prevention of spinal anaesthesia-induced hypotension in the elderly: i.m. methoxamine or 
combined hetastarch and crystalloid. Br J Anaesth. 1998 Feb;80(2):199-203. 
14.    Kyokong O, Charuluxananan S, Sriprajittichai P, Poomseetong T, Naksin P. The incidence and risk factors of hypotension and bradycardia associated with spinal 
anesthesia. J Med Assoc Thai. 2006 Sep;89 Suppl 3:S58-64. 
15.    Ngan Kee WD. Prevention of maternal hypotension after regional anaesthesia for caesarean section. Current Opinion in Anesthesiology 2010; 23: 304–9. 
16.    Lewinsky RM, Riskin-Mashiah S. Autonomic imbalance in preeclampsia: evidence for increased sympathetic tone in response to the supine-pressor test. 
Obstetrics and Gynecology 1998; 91: 935–9. 
17.    Li P, Tong C, Eisenach JC. Pregnancy and ephedrine increase the release of nitric oxide in ovine uterine arteries. Anesthesia and Analgesia 1996; 82: 288–93. 
18.    Sia AT, Tan HS, Sng BL. Closed-loop double-vasopressor automated system to treat hypotension during spinal anaesthesia for caesarean section: a preliminary 
study. Anaesthesia. 2012 Dec;67(12):1348-55. doi: 10.1111/anae.12000. Epub 2012 Sep 28. 
19.    Ilies C, Kiskalt H, Siedenhans D, et al. Detection of hypotension during Caesarean section with continuous non-invasive arterial pressure device or intermittent 
oscillometric arterial pressure measurement. Br J Anaesth 2012;109:413–9. 
20.    Sng BL, Wang H, Assam PN, Sia AT. Assessment of an updated double-vasopressor automated system using Nexfin for the maintenance of haemodynamic 
stability to improve peri-operative outcome during spinal anaesthesia for caesarean section. Anaesthesia. 2015 Jun;70(6):691-8. doi: 10.1111/anae.13008. Epub 2015 
Jan 28. 
21.   Sng BL, Du W, Lee MX, Ithnin F, Mathur D, Leong WL, Sultana R, Han NLR, Sia ATH. Comparison of double intravenous vasopressor automated system using 
Nexfin versus manual vasopressor bolus administration for maintenance of haemodynamic stability during spinal anaesthesia for caesarean delivery: A randomised 
double-blind controlled trial. Eur J Anaesthesiol. 2018 May;35(5):390-397. 
22.  Struys MM, De Smet T, Greenwald S, Absalom AR, Bingé S, Mortier EP. Performance evaluation of two published closed-loop control systems using bispectral 
index monitoring: a simulation study. Anesthesiology. 2004 Mar;100(3):640-7.