A Double-Blind, Randomized Control Trial of Rapidly Infused High Strong Ion Difference Fluid Versus Hartmann's Solution on Acid-Base Status in Sepsis and Septic Shock Patients in the Emergency Department Hospital Pulau Pinang
Phase: NA
Conditions: Septicemic Shock
Sponsor: Clinical Research Centre, Malaysia

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 1 of 32 
Short title: HiSIDSS. 
 
Protocol number: ED-HPP-1701 (15th Jan 2017) 
NCT number: NCT03530046 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Double-Blind, Randomized Control Trial of Rapidly Infused High Strong Ion 
Difference Fluid versus Hartmann’s solution on Acid-Base Status in Sepsis and 
Septic Shock Patients in the Emergency Department Hospital Pulau Pinang 
 
 

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 2 of 32 
Short title: HiSIDSS. 
 
Confidentiality Statement 
May not be used, divulged, published or otherwise disclosed without the 
written consent of the Principal Investigator. 

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 3 of 32 
Short title: HiSIDSS. 
 
v 
 
Study Title: A Double-Blind, Randomized Control Trial of Rapidly Infused High 
Strong Ion Difference Fluid versus Hartmann’s solution on Acid-Base Status in 
Sepsis and Septic Shock Patients in the Emergency Department Hospital Pulau 
Pinang 
 
Clinical study protocol number/version: ED-HPP-1701 
 
Development phase: Ethics approval 
 
Study initiation date: 1st Feb 2017  
Study completion date: 31st Jan 2018  
Date of protocol: 24 Oct 2016 
Amendment  number(s) and date : Version 1.0 (15th Jan 2017) 
 
Author(s) : Dr. Yeoh Chun Chiat 
Author’s and Reviewer’s signature and date: 
Protocol Author 
Reviewed and approved by 
Signature: 
Signature: 
Date: 
Date: 
 
 
This protocol incorporates the following amendment(s): 
 
Amendment No. 
Date of Amendment 
Initials of 
Principal Investigator 
1 
15/1/2017 
 
 
 
 
 

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 4 of 32 
Short title: HiSIDSS. 
 
1 SYNOPSIS 
 
Title of study: 
A Double-Blind, Randomized Control Trial of Rapidly Infused High Strong Ion 
Difference Fluid versus Hartmann’s solution on Acid-Base Status in Sepsis 
and Septic Shock Patients in the Emergency Department Hospital Pulau 
Pinang 
 
 
Sponsor: Self funding 
 
Clinical Phase: 
     Non- applicable 
Investigators: 
Name and institution of Principal investigator: 
Chun Chiat Yeoh, Emergency Physician Trainee, Emergency Department, Hospital 
Pulau Pinang. 
 
Name and Institution of Co-Investigators: 
1. Aik Howe Teo, Consultant Emergency Physician, Emergency Department, 
Hospital Pulau Pinang 
2. Sasi Kumar A/L Sappanie, Senior Medical Officer, Emergency Department, 
Hospital Pulau Pinang. 
3. Sherene Tan Su Ann, Pharmacist, Pharmacy Department, Hospital Pulau 
Pinang.  
4. Abdul Muhaimin bin Noor Azhar, Emergency Physician and Lecturer, 
Emergency Department, University of Malaya 
 
Study period:  1 year 
Planned date of first subject enrolment: 1st Feb 2017 
Planned date of last subject completed: 31st Jan 2018 
 
Objectives: 
Primary objective: 
To determine the mean difference of blood pH and bicarbonate level at 2 hours or 
after 30ml/kg administration of high SID fluid or Hartmann’s Solution (whichever 
occurs first).  
 
    Secondary objectives: 
 
To determine: 
➢ the mean difference in lactate level at 2 hours,  
➢ all-cause mortality at 30 days, 
➢ development of pulmonary edema,  
➢ the mean length of stay in hospital,  
➢ the incidence of acute kidney injury (AKI) as defined by the AKIN criteria 
of high SID fluid and Hartmann’s Solution 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 5 of 32 
Short title: HiSIDSS. 
 
 
Methodology: 
The study is a double-blind randomized controlled trial with parallel design and an 
allocation ration of one to one. Eligible subjects are assigned in a 1:1 ratio by 
means of randomization using online randomizer, http://www.randomiser.com. The 
code is saved in the randomization log which will only be secured by an assigned 
pharmacist. A trained nurse or pharmacist will prepare the study fluids (either half 
saline with addition of 75mEq/L sodium bicarbonate or Hartmann’s solution) 
according to the randomization list right after a suitable patient is recruited.  
Blinding will be achieved by using unlabeled 500cc saline bottle. The study fluids 
will be macroscopically indistinguishable.  
All clinicians, patients and investigators will be blinded for the coding of the study 
fluids used during resuscitation. Unblinding of the code will be only done after 
analysis of the primary outcome was completed except for rare emergency cases 
when treating physician believes that clinical management depends importantly 
upon knowledge of whether the patient received high SID fluid or Hartmann’s 
solution. 
Subjects receive study fluid and the rate of infusion depends on clinical judgment 
by the treating physician. Each subject is monitored every 30 minutes for blood 
pressure, pulse volume and capillary refill time. Blood samples are taken for 
electrolytes, urea and creatinine measurement, blood gas analysis with lactate at 
baseline before the initiation of study fluid. When 30ml/kg of study fluid is 
administered or at 2 hours (whichever occurs first), another blood gas with lactate 
will be taken. Study fluid may be discontinued depending on the clinician’s 
judgement. If the study fluid needs to be discontinued, the total amount of test fluid 
will be recorded and the subject will be excluded from the analysis. 
 
Subjects are subsequently followed up in the ward for BUSEC within 48 hours and 
for all-cause mortality in 30 days. 
 
At least one trained staff member will be available throughout the intervention 
period. 
 
 
Number of patients: 
162 patients. 
 
 
Number of centre(s): 
1 
Inclusion criteria: 
• 
age≥18 years  
• 
fulfills 2/3 qSOFA criteria 
• 
presumed infection 
• 
a blood pH at presentation ≤ 7.35 
• 
hyperlactatemia (blood lactate level, >2mmol/L) 
 
Exclusion criteria: 
• 
existing cardiac failure, major cardiac arrhythmia, advanced chronic kidney 
disease or end stage failure  
• 
known pregnancy 
• 
suspected dengue  
• 
primary diagnosis is related to burn, trauma, or drug overdose  
• 
if more than 500cc of resuscitation fluid was administered before 
enrolment. 
 
 

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 6 of 32 
Short title: HiSIDSS. 
 
 
 
 
Test treatment, dose and mode of administration: 
High SID fluid (half saline with addition of 75 mEq/L sodium bicarbonate), administered 
via intravenous infusion.  
 
Dose: 30ml/kg or after 2 hours administration, whichever occurs first 
 
Duration of treatment with study medication: 
2 hours 
 
 
Criteria for evaluation: 
1. The primary clinical outcome was change of blood pH and bicarbonate level at 2 
hours or after 30ml/kg of test fluid administered, whichever is earlier.  
2. Secondary outcomes 
a.  the change in lactate level at 2 hours or after 30ml/kg of test fluid 
administered, whichever is earlier,  
b. all-cause mortality at 30 days, 
c. development of pulmonary edema,  
d. length of stay in hospital,  
e. the incidence of acute kidney injury (AKI) as defined by the AKIN criteria 
 
 
Statistical methods: 
1. Sample size is calculated using PS software. The sample size calculation assumed 
the following: α value 0.05, power of 0.95 and standard deviation of 0.05 from 
previous study (26). It is powered to detect a 0.03 difference in pH between 2 
study fluids. The calculated sample size was 73 patients each arm with total 146 
patients. Considering drop-out rate of 10%, total sample size is 162 (81 patients 
each arm). 
2.  Data analysis will be performed using the SPSS program. Descriptive analysis will 
be used to describe demographic and disease characteristics of the patients. 
Percentages and frequencies will be used for categorical variables while means 
and standard deviations will be calculated for continuous variables. The 
significance level is set at p-value less than 0.05. 
3. The mean difference of blood pH, bicarbonate level and lactate level between the 
two study fluids will be analyzed using Independent T-test (normally distributed) 
or Mann-Whitney Test (non-normally distributed). 
4. The all-cause mortality at 30 days, development of pulmonary edema and 
incidence of acute kidney injury will between the two study fluids will be analyzed 
using binary logistic regression. 
5. The length of stay in hospital between the two study fluids used will be analyzed 
using Independent T-test (normally distributed) or Mann-Whitney Test (non-
normally distributed). 
 
 
-End- 

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 7 of 32 
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3 TABLE OF CONTENTS 
1 
CONFIDENTIALITY STATEMENT ...................................................................................... 1 
2 
SYNOPSIS ................................................................................................................................. 2 
3 
TABLE OF CONTENTS .......................................................................................................... 6 
4 
LIST OF ABBREVIATIONS.................................................................................................... 9 
5 
GLOSSARY OF TERMS ........................................................................................................ 10 
6 
ETHICS & REGULATORY CONSIDERATIONS ............................................................... 11 
6.1 INDEPENDENT ETHICS COMMITTEE ..................................................................................... 11 
6.2 ETHICAL CONDUCT OF THE STUDY ....................................................................................... 11 
6.3 INFORMED CONSENT AND SUBJECT INFORMATION ............................................................... 11 
6.4 PATIENT PROTECTION PROCEDURES .................................................................................... 12 
6.4.1 
PROCEDURES IN THE EVENT OF EMERGENCY ........................................................................ 12 
6.4.2 
PROCEDURES IN THE EVENT OF PREGNANCY ........................................................................ 12 
6.4.3 
PATIENT DATA PROTECTION ................................................................................................. 13 
7 
INTRODUCTION AND BACKGROUND ............................................................................. 14 
 
7.1 
POTENTIAL RISK ........................................................................................................................................... 15 
7.2 
POTENTIAL BENIFITS ................................................................................................................................... 15 
8 
OBJECTIVES ......................................................................................................................... 15 
8.1 PRIMARY OBJECTIVE ............................................................................................................ 15 
8.2 SECONDARY OBJECTIVE(S): .................................................................................................. 15 
9 
STUDY DESIGN ..................................................................................................................... 16 
9.1 OVERALL STUDY DESIGN....................................................................................................... 16 
9.2 SCHEMATIC DIAGRAM OF STUDY DESIGN ............................................................................. 16 
9.3 DISCUSSION OF STUDY DESIGN .............................................................................................. 16 
9.4 STUDY POPULATION .............................................................................................................. 17 
9.4.1 
INCLUSION CRITERIA ........................................................................................................... 17 
9.4.2 
EXCLUSION CRITERIA .......................................................................................................... 17 
9.4.3 
SUBJECT WITHDRAWAL & DROP-OUT ................................................................................... 17 
9.4.4 
PROCEDURES FOR HANDLING WITHDRAWAL ........................................................................ 17 
9.4.5 
SUBJECT REPLACEMENT POLICY........................................................................................... 17 
9.4.6 
SCREENING FAILURES .......................................................................................................... 18 
10 
TREATMENT AND STUDY PROCEDURES ..................................................................... 18 
10.1 
DESCRIPTION OF STUDY FLUID/INTERVENTION .................................................................. 18 
10.2 
COMPARATOR DRUG/INTERVENTION .................................................................................. 18 
10.3 
DOSAGE AND ADMINISTRATION……………………………………………………………………………. 18 
10.4 
INVESTIGATIONAL PRODUCT SUPPLY AND HANDLING ........................................................ 18 

Clinical Study Protocol  
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10.4.1 
SUPPLY, PACKAGING AND LABELLING ................................................................................ 18 
10.4.2 
STORAGE ........................................................................................................................... 18 
10.4.3 
DISPENSING ....................................................................................................................... 19 
10.5 
CONCOMITANT MEDICATION/TREATMENT ......................................................................... 19 
10.6 
TREATMENT ALLOCATION AND RANDOMISATION ............................................................... 19 
10.7 
BLINDING & EMERGENCY UNBLINDING PROCEDURES ........................................................ 19 
10.8 
BASSELINE ASSESSMENT AND LABORATORY TEST .............................................................. 20 
10.9 
DISCONTINUATION AND INTERRUPTION OF TREATMENT ................................................... 20 
10.10 ASSESSMENT OF EFFICACY .................................................................................................. 20 
10.11 ASSESSMENT OF SAFETY ..................................................................................................... 20 
11 
ADVERSE EVENTS ............................................................................................................. 21 
11.1 
DEFINITIONS........................................................................................................................ 21 
11.1.1 
ADVERSE EVENT (AE) ........................................................................................................ 21 
11.1.2 
UNEXPECTED ADVERSE EVENT ........................................................................................... 21 
11.1.3 
SERIOUS ADVERSE EVENT (SAE) ........................................................................................ 21 
11.2 
DETECTING AND DOCUMENTING AE ................................................................................... 22 
11.3 
REPORTING SAE ................................................................................................................. 23 
11.4 
TREATMENT AND FOLLOW UP OF AE .................................................................................. 24 
11.5 
SAFETY UPDATE .................................................................................................................. 24 
12 STUDY CONDUCT .............................................................................................................. 25 
12.1 
STUDY PROCEDURES ........................................................................................................... 25 
12.1.1 
BASELINE DATA AND LABORATORY INVESTIGATIONS ......................................................... 25 
12.1.2 
RANDOMISATION ............................................................................................................... 25 
12.1.3 
FOLLOW UP ........................................................................................................................ 26 
12.2 
CRITERIA FOR STOPPING SUBJECT TREATMENT ................................................................. 26 
12.3 
SAMPLE HANDLING AND ANALYSIS ..................................................................................... 26 
12.3.1 
COLLECTION ...................................................................................................................... 26 
12.3.2 
LABELLING ........................................................................................................................ 26 
12.4 
LABORATORY ANALYSIS ..................................................................................................... 26 
13 DATA MANAGEMENT ....................................................................................................... 26 
14 STATISTICAL METHODS ..........................................................................................27 
14.1 
SAMPLE SIZE AND POWER CONSIDERATIONS ...................................................................... 27 
14.2 
RANDOMISATION ................................................................................................................. 27 
14.3 
ANALYSIS ............................................................................................................................ 27 
15 ADMINISTRATIVE MATTERS ......................................................................................... 27 
15.1 
NOTIFICATION OF REGULATORY AUTHORITIES.................................................................. 27 
15.2 
STUDY INITIATION ............................................................................................................... 27 
15.3 
PROTOCOL DEVIATION ........................................................................................................ 27 
15.4 
STUDY DOCUMENTATION .................................................................................................... 28 
15.4.1 
ESSENTIAL DOCUMENTS..................................................................................................... 28 
15.4.2 
SOURCE DOCUMENTS ......................................................................................................... 28 
15.5 
PATIENT IDENTIFICATION LIST/ENROLLMENT LOG ........................................................... 29 
15.6 
CURRICULUM VITAE ........................................................................................................... 29 

Clinical Study Protocol  
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Page 9 of 32 
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15.7 
SITE SIGNATURE/AUTHORIZATION LOG .............................................................................. 29 
15.8 
MONITORING THE STUDY .................................................................................................... 29 
15.9 
AUDITS AND INSPECTIONS ................................................................................................. 29 
15.10 
RETENTION OF DOCUMENTS ............................................................................................. 29 
15.11 
FINANCE ............................................................................................................................ 30 
15.12 
STUDY TERMINATION AND SITE CLOSURE ........................................................................ 30 
15.13 
CONFIDENTIALLY .............................................................................................................. 30 
15.14 
PUBLICATION POLICY ....................................................................................................... 30 
15.15 
ANTICIPATED SUBJECT ACCRUAL AND DURATION OF THE STUDY .................................... 30 
16 REFERENCES ...................................................................................................................... 31 
17 APPENDICES ....................................................................................................................... 32 

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 10 of 32 
Short title: HiSIDSS. 
 
4 LIST OF ABBREVIATIONS 
 
0C 
Degree Centigrade 
AE 
Adverse event 
BP 
Blood pressure 
BUSEC 
Blood for urea, serum electrolytes and creatinine level 
CRF 
Case report form 
CV 
Curriculum vitae 
GCP 
Good clinical practice 
IEC 
Independent Ethics Committee 
ID 
Identification 
IRB 
Independent Review Board 
mmHg 
Millimeter mercury 
SAE 
Serious adverse event 
  SID  
  Strong Ion Deficit 

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 11 of 32 
Short title: HiSIDSS. 
 
5 GLOSSARY OF TERMS 
 
(Comprehensive list of commonly used terms is found in Malaysian Guidelines for 
GCP) 
 
 
Eligible 
Qualified for enrolment into the study based on strict adherence 
to inclusion and exclusion criteria. 
 
Evaluable 
Meeting all eligibility criteria, complying with the procedures 
defined in the protocol and therefore included in analysis. 
 
Investigator 
Treating physician 
 
Protocol 
Any  change  in  a  study  protocol  which  affects  the  safety  of 
amendment 
subjects, the scope, design, assessments or scientific validity  of 
the clinical investigation. 
 
Subject(s) 
Individuals enrolled in the clinical study. 

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 12 of 32 
Short title: HiSIDSS. 
 
6 
ETHICS & REGULATORY CONSIDERATIONS 
6.1    Independent Ethics Committee 
The study protocol and any other documents that the IEC may need to fulfil its 
responsibilities including the Patient Information Sheet, Consent Form,  subject 
requirement procedures and advertisements to be used, and information on 
payments and compensation available to subjects, will be submitted to a 
properly constituted Independent Ethics Committee (IEC). Unconditional 
approval or a favourable opinion must be received from the IEC before 
commencement of this study. Approval from the committee must be 
documented in a letter to the investigator specifying the study title, protocol 
number, the documents reviewed, the date on which the committee met and 
granted the approval, the name, occupation and institutional affiliation of the 
chairman and members of the IEC, and provisions for periodic review if any. 
Any amendments to the protocol, other than administrative ones, must also be 
approved by this committee. 
 
The principal investigator will inform the IEC of: 
➢ Any amendment to the protocol, informed consent changes or revisions of 
other documents originally submitted for review. 
➢ Any serious and/or unexpected events occurring during the study, where 
required. 
➢ Any new information that may adversely affect the safety of the subjects or 
the conduct of the study. 
➢ An annual update on the progress of the study and/or request for re- 
approval, where required. 
➢ Final study report when the study has been completed, where required. 
 
All correspondence with the IEC should be filed by the principal investigator in 
the Investigator's Study File. 
 
 
6.2 
Ethical conduct of the study 
The study will be conducted in compliance with the protocol and CRC standard 
operating procedures. These are designed to ensure adherence to the ethical 
principles that have their origin in the "World Medical Association Declaration 
of Helsinki" (see Appendix), "Malaysian Guidelines for Good Clinical Practice" 
and applicable regulatory Requirements. 
 
 
6.3 
Informed consent and subject information 
Freely given informed consent must be obtained from every subject prior to 
participation in this study. The investigator must inform every subject in detail 
about the nature of the study, its purpose, the treatments and the probability of 
random assignment to treatment groups, those aspects of the study that are 
experimental, the procedures involved including all invasive procedures and the 
discomfort they may entail, the reasonably expected benefits the expected 
duration and the approximate number of subjects involved and the subject's 
responsibilities. 
 
 
 
 
 

Clinical Study Protocol  
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Page 13 of 32 
Short title: HiSIDSS. 
 
Study subjects must also be informed that: 
➢ Participation in this study is voluntary and that he/she may withdraw from 
this study at any time for any reason and that withdrawal of consent will  not 
affect his/her subsequent medical treatment or relationship with the treating 
physician. 
➢ They will be notified in a timely manner if information becomes available that 
may be relevant to their willingness to continue participation in the study. 
➢ Alternative procedures or treatments that may be available and the 
important potential benefits and risks of these available alternative 
procedures or treatments. 
➢ Any compensation for additional costs and/or injury caused to a subject 
attributable to participation in the study. 
➢ Financial expenses, if any, to the subject for participating in the study as 
well as prorated payment, if any, to the subject for participating in the study. 
➢ Any foreseeable circumstances and/or reasons under which the subject's 
participation in the study may be terminated. 
➢ The person(s) to contact for further information regarding the study and 
whom to contact in the event of study related injury. 
 
Written consent will be obtained from each subject involved in the study. If 
written consent from the subject is not possible, written consent can be obtained 
from the subject’s representative who is subject’s parent or guardian, stating 
why the patient was unable to sign the consent form. The informed consent 
form used to document written or oral consent in the study must be received 
prior to approval from the IEC. If the subject and his/her representative are 
unable to read, the investigator or designee must explain to the subject the 
content of the Patient Information Sheet and Consent Form point by point in the 
presence of an impartial witness. The witness should personally sign and date 
the consent form. The potential study subject and/or his/her parent/guardian 
should be given the opportunity to ask questions and time for consideration. 
 
A copy of the Patient Information Sheet and signed Consent Form should be 
given to the subject or subject’s parent/guardian if patient was unable to sign 
the consent form. The original must be filed by the principal investigator in the 
Investigator's Study File. A sample of the Patient Information Sheet and 
Consent Form can be found in the Appendix of this protocol. 
 
6.4 
Patient protection procedures 
6.4.1 Procedures in the event of Emergency 
The investigator is responsible for ensuring that procedures and expertise are 
available to cope with medical emergencies during the study. An emergency 
may constitute an SAE. 
 
6.4.2 Procedures in the event of Pregnancy 
The subject must be instructed to inform the investigator if she becomes 
pregnant during the study and seek advice regarding continuation of the study 
treatment. The investigator should follow up the pregnancy until the outcome is 
known. 
 
 
 
 
6.4.3 Patient data protection 
The investigator must assure that the subjects' anonymity will be maintained 

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 14 of 32 
Short title: HiSIDSS. 
 
and that the confidentiality of records and documents that could identify 
subjects will be protected, respecting the privacy and confidentiality rules in 
accordance with applicable regulatory requirements. 
 
➢ Subjects must be identified only by their assigned identification number and 
initial on all CRFs 
➢ The investigator will keep a Patient Identification List with complete 
identification information (name, address, contact number, NRIC number) 
on each subject. 
➢ Documents not for submission to CRC such as subject's written 
informed consent form, will be maintained by the investigator in strict 
confidence. 
 
All the data will be stored in a password encrypted computer which only the 
principle and co-investigators has access to it. The data will be analyzed by SPSS 
software using the same computer. Once data analysis is completed, the data will 
be transferred to password encrypted CD and will be kept in the high security safe 
in the Emergency Department, Hospital Pulau Pinang. 
 
 

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Page 15 of 32 
Short title: HiSIDSS. 
 
7 
INTRODUCTION AND BACKGROUND 
 
Intravenous administration of saline has become a routine component in 
resuscitating critically ill adult patients in emergency department. Fluid 
resuscitation using saline was first described in 1831 during the Cholera 
endemic.(1) Since then, saline use for replacement or maintenance became the 
mainstay of critical care. In patients with sepsis and septic shock especially, large 
volume resuscitation in early stage up to 30ml/kg is crucial in maintaining the 
hemodynamical stability and to improve survival. (2) Therefore, the selection and 
administration of resuscitation fluids in septic patients is crucial and must be 
tailored according to patients’ situation (3).  
Stewart pointed out that whole body acid–base balance is mainly regulated by 
strong ion movements through membranes (4). The crystalloid strong ion 
difference (SID) is the net electrical charge difference of the infusate strong cations 
minus the anions. The traditional saline-based fluid resuscitation strategy, 
however, fails to link the physicochemical properties of the crystalloid solution or 
crystalloid strong ion difference (SID).(5,6,7)  
Large volume saline-based resuscitation was found to cause hyperchloreamic 
acidosis in both abdominal and gynecological surgery patients. (8,9) High chloride 
content, the dilution effect due to extravascular bicarbonate, and a strong ion 
difference (SID) per Stewart’s formula have been implicated as the causes of 
acidosis.(10) Hyperchloraemia will alter tubuloglomerular feedback by causing 
renal vasoconstriction,(11) decreased renal artery flow velocity, blood flow, and 
cortical tissue perfusion,(12) and ultimately reduced glomerular filtration rate,(13) 
leading to salt and water retention.  
Several studies evaluating the relationship between choices of fluid in 
resuscitation and metabolic acidosis have been conducted. When compared with 
crystalloids, colloids have not been shown to improve patient-centred outcomes. 
(14) On the other hand, recent literatures showed that among all the choices of 
crystalloids, balanced saline for example hartmanns’ solution, is superior in terms 
of higher survival rate and lower incidence of kidney injury(15-20), due to its 
similarity to human plasma in their composition and higher strong ion difference, 
Up to date, there are 2 recognised high SID fluids available in the market, namely 
Normosol and Plasmalyte. Shin et al(21) had showed that intraoperative fluid 
resuscitation wih high SID fluid is associated with lower lactate level post-surgery 
which is vital to improve the survival outcomes. High SID fluids also were proven 
to better choice in term of reducing the rate of acute kidney injury  as they do not 
produce hyperchloraemia and acidosis.(12, 22)  
 
Study by Omron and colleagues (23) showed that solutions whose SID was 
greater than 24.5 mEq/L such as one-half normal saline with addition of 75mEq/L 
sodium bicarbonate (SID= 75mEq/L) demonstrated a progressive metabolic 
alkalosis and less progressive metabolic acidosis. Kiran et al (24) demonstrated 
metabolic acidosis in critically ill patients especially with sepsis with septic shock 
was associated with statistically significant mortality up to 70% which is also 
consistent with the previous study by Jung et al. (25) 
  
The aim of the study was to determine whether, among patients with severe sepsis 
and septic shock who needs initial high volume resuscitation, the use of high SID 
intravenous solution i.e. one-half normal saline with addition of 75mEq/L sodium 
bicarbonate (SID = 75 mEq/L) as an early fluid choice, when compared with 
Hartmann solution (SID = 28 mEq/L) is associated with greater change in body pH 
and bicarbonate level as well other adverse outcomes.  
 
 

Clinical Study Protocol  
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7.1 Potential Risks 
Patient might sustain superficial hematoma after venipuncture for blood 
sampling. Extravasation of study fluid might occur during infusion. Supportive 
management will be given to minimize the damage should the risks occur.  
 
7.2 Potential Benefits 
From the previous literatures, both study fluids are proven to be safe and 
beneficial to patients. 
High SID fluid is hypothesized to normalise the metabolic acidosis faster and to 
the greater extend as compared to Hartmann’s Solution.  
 
 
8 OBJECTIVES 
8.1 
Primary objective: 
To determine the mean difference of blood pH and bicarbonate level at 2 hours 
or after 30ml/kg administration of high SID fluid or Hartmann’s Solution 
(whichever occurs first).  
 
8.2 
Secondary objective(s): 
To determine: 
➢ 
the mean difference in lactate level at 2 hours,  
➢ 
all-cause mortality at 30 days, 
➢ 
development of pulmonary edema,  
➢ 
the mean length of stay in hospital,  
➢ 
the incidence of acute kidney injury (AKI) as defined by the AKIN criteria 
of high SID fluid and Hartmann’s Solution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9 
STUDY DESIGN 
9.1 
Overall study design 
A Double-blind, Randomized Control Trial 
 
 
9.2 
Schematic diagram of study design: 
 
 
9.3 
Discussion of study design 
The study is a double-blind randomized controlled trial with parallel design and 
an allocation ration of one to one. Eligible subjects are assigned in a 1:1 ratio by 
means of randomization using online randomizer, http://www.randomiser.com. 
The code is saved in the randomization log which will only be secured by an 
assigned pharmacist. A trained nurse or pharmacist will prepare the study fluids 
(either half saline with addition of 75mEq/L sodium bicarbonate or Hartmann’s 
solution) according to the randomisation list right after a suitable patient is 
recruited.  
Standard 500cc half saline bottle and hartmann’s solution will be used during the 
study. The trained nurse or pharmacist will completely tear off the labels on the 
bottle replace it with a label with only randomisation number and patient’s ID. As 
for the investigational fluid regime, the trained nurse or pharmacist will initially 
draw out 37.5mls of half saline and then replace it with 37.5mls of sodium 
bicarbonate 8.4%. At the end of preparation, the study fluids will be 
macroscopically indistinguishable.  
All clinicians, patients and investigators will be blinded for the coding of the study 
fluids used during resuscitation. Unblinding of the code will be only done after 
analysis of the primary outcome was completed except for rare emergency 
cases when treating physician believes that clinical management depends 
importantly upon knowledge of whether the patient received high SID fluid or 
Hartmann’s solution. 

Clinical Study Protocol  
Study Code: ED-HPP-1701 
Page 18 of 32 
Short title: HiSIDSS. 
 
Subjects receive study fluid and the rate of infusion depends on clinical judgment 
by the treating physician. Each subject is monitored every 30 minutes for blood 
pressure, pulse volume and capillary refill time. Blood samples are taken for 
electrolytes, urea and creatinine measurement, blood gas with lactate at 
baseline before the initiation of study fluid. When 30ml/kg of study fluid is 
administered or at 2 hours (whichever occurs first), another blood gas with 
lactate will be taken. Study fluid may be discontinued depending on the 
clinician’s judgement. If the study fluid needs to be discontinued, the total amount 
of test fluid will be recorded and the subject will be excluded from the analysis. 
At the end of 2 hours of resuscitation or after 30ml/kg of study fluid is 
administered, subjects will be given the usual resuscitation fluid according to the 
treating physician’s judgement.   
Subjects are subsequently followed up in the ward for BUSEC within 48 hours 
and for all-cause mortality in 30 days. 
At least one trained staff member will be available throughout the intervention 
period. 
 
9.4 
Study population 
All eligible patients including ventilated patients admitted to Emergency 
Department with severe sepsis or septic shock within the study period. 
9.4.1 Inclusion criteria 
• 
age≥18 years  
• 
fulfills 2/3 qSOFA criteria 
• 
presumed infection  
• 
a blood pH at presentation ≤ 7.35 
• 
hyperlactatemia (blood lactate level, >2mmol/L) 
*according to Third International Consensus Definitions for sepsis and septic 
shock 2016 (Sepsis 3), qSOFA criteria are Respiratory rate more than 22 
breath per minute, systolic blood pressure less than 100mmHg and altered 
GCS. Score of 2 or more is associated with mortality rate more than 10%. 
 
9.4.2 Exclusion criteria 
• 
existing cardiac failure, major cardiac arrhythmia, advanced chronic 
kidney disease or end stage failure  
• 
known pregnancy 
• 
suspected dengue (patient who fulfilled the criteria of probable dengue   
at presentation) 
• 
primary diagnosis is related to burn, trauma, or drug overdose  
• 
if more than 500cc of resuscitation fluid was administered before 
enrolment. 
 
9.4.3 Subject withdrawal & drop-out 
All subjects can choose to withdraw at any time.  
Study fluid may be discontinued depending on the clinician’s judgement. If the 
study fluid needs to be discontinued, the total amount of test fluid will be recorded 
and patient will be excluded from the analysis. 
 
9.4.4 Procedures for handling withdrawal 
Subjects who withdraw or are withdrawn from the study should have the 
reason(s) for their withdrawal recorded 
 
9.4.5 Subject replacement policy 
  
 Withdrawn subjects will not be replaced. 
9.4.6 Screening failures 

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Patients who fail to meet the inclusion and exclusion criteria are defined as 
screening failures. The investigator will maintain a Screening Log which 
includes screen failures. The log will document the subject number, subject 
initials, demographics and the reason(s) for excluding the patient from the 
study. This log will be kept in the Investigator's Study File. It will be used to 
determine systematic bias in selection of patients for entry into the study. 
 
 
10. TREATMENT AND STUDY PROCEDURES 
10.1 Description of study fluid/intervention 
Standard 500cc Half saline bottle (INFUSOL ® HS) will be used as study fluid. 
To create a high SID fluid with SID of 75, 75mEq/L of sodium bicarbonate will be 
added to the 500cc bottle of half saline, which is equivalent to 37.5mls of 8.4% 
sodium bicarbonate.  
 
10.2 Comparator of study fluid/intervention 
Standard 500cc bottle Hartmann’s solution (INFUSOL ® HM) which contains 
sodium chloride 600mg/100ml and calcium chloride 27mg/100ml, potassium 
chloride 40mg/100ml, sodium lactate 320mg/ml. 
 
10.3 Dosage and administration  
Group 1: 30ml/kg of IVD half-normal saline with addition of 75mEq/L sodium 
bicarbonate  
 
Group 2: 30ml/kg of IVD Hartmann’s Solution.  
The rate of infusion of study fluids will be given depending on treating physician 
clinical judgement.   
 
The study fluids will be given via volumetric infusion pump available in 
Emergency Department Hospital Pulau Pinang. 
 
10.4 Investigational product supply and handling 
10.4.1 Supply, packaging and labelling 
Each study fluid will be labelled with the following information: 
10.4.1.1 
Manufacturer's identification 
10.4.1.2 
Protocol number 
10.4.1.3 
'For Clinical Trial Use Only' statement 
10.4.1.4 
Randomisation number 
10.4.1.5 
Subject’s ID 
10.4.1.6 
Quantity of bottles 
10.4.1.7 
Storage conditions 
10.4.1.8 
Expiry date 
 
10.4.2 Storage 
The investigational product must be stored in accordance with the 
manufacturers' instructions. Required conditions for storage will be printed on 
the medication label. Until the investigational product is dispensed, it must be 
stored at room temperature below 30oC.  
Investigational product should be kept under adequate security by the 
investigator and only accessible to authorised study personnel. 
10.4.3 Dispensing 

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Upon dispensation, the investigator must write the following in the 
Investigational Product Dispensing Log: subject ID and initials and date 
dispensed, total bottles dispensed, batch number and expiry date of product. 
 
 
10.4.4 Accountability  
The investigator or designee must maintain current and accurate record of the receipt, 
inventory and dispensing, including shipping invoices, of all study supplies. The 
Investigational Product Accountability Log must include:  
o 
Date received  
o 
Name of study medication and dosage  
o 
Amount currently in storage area  
o 
Label ID number or batch number/Lot number 
o 
Name and initial of person responsible for each investigational product inventory 
entry/movement 
o 
Amount dispensed to and returned by each subject, including unique subject 
identifiers  
o 
Amount transferred to another area for dispensing or storage  
o 
Non-study disposition (eg. Lost, wasted, broken)  
o 
Amount destroyed at study site  
o 
Accountability logs must be available for inspection by CRC monitor at any time. Upon 
completion/termination of the study, unused investigational product must be returned 
to the sponsor or CRC for reconciliation and destruction. 
 
10.5 Concomitant medication/ treatment 
The rate of infusion, time of initiating antibiotics, inotropes will not be 
interfered by commencement of study fluid. 
 
10.6 Treatment allocation and randomization 
• Patients were assigned in a 1:1 ratio by means of randomization using 
online randomizer, http://www.randomiser.com/. 
• The code is saved in the randomization log which will only be secured 
by an pharmacist assigned by the Principal Investigator. 
• Each time when patient is recruited, a trained pharmacist or senior 
nurse or senior medical officer who is not involved directly in the 
treatment of the subject will open the randomization log and prepare 
the test fluid according to the randomization log. 
• The following information will be recorded during randomization: 
a. Study ID (assigned during study initiation) 
b. Subject's screening status 
c. Date of informed consent signed by subject 
d. Subject's ID no.  
e. Upon successful randomization, the subject will be assigned a 
randomization number and study fluid.  Document the subject's ID 
no.  and randomization no. on the Patient Enrolment Log and 
Patient Identification List. 
 
10.7 Blinding & emergency unblinding procedures 
 
All the investigators, treating physician and subjects will be blinded to the study 
fluid which is given during the treatment.  
Generally there should be no need to unblind the allocated study fluid. 
Unblinding should only be done only in those rare cases in the event that an AE 
which knowledge of the identity of the test drug is necessary to manage the 
subject's condition, the treating physician will call the Principal Investigator who 
will review actual type study fluid given to that subject, identify the test drug 

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Study Code: ED-HPP-1701 
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immediately. The Principal Investigator will decide whether unblinding is 
required. 
A detailed report with the date and reason for identifying the study drug will be 
prepared by the Principal Investigator and informed to IEC. This report must be 
signed by the treating physician and the Principal Investigator.  
 
Except in the rare emergency cases, the treatment blind will be maintained until 
all subjects have completed the treatment and the database has been cleaned 
and locked.  
 
10.8 Baseline assessment and laboratory tests  
Baseline parameters and laboratory tests as below will be captured in 
entry form:  
• Social demographics, weight and height 
• Co-morbid factors  
• Primary disease  
• Drug history  
• Laboratory data 
 
10.9 Discontinuation and interruption of study fluid infusion 
Study fluid may be discontinued depending on the clinician’s judgement. If the 
study fluid needs to be discontinued, the total amount of test fluid will be recorded 
and patient will be excluded from the analysis. 
 
10.10 Assessment of efficacy 
The outcomes of the study are assessed using specific efficacy parameter: 
10.10.1 Primary end-point: change in pH and bicarbonate level post 
study fluid infusion 
10.10.2 Secondary end-point: change in lactate level post study fluid 
infusion 
 
10.11 Assessment of safety 
Safety assessments will consist of: 
10.11.1 Monitoring and recording all adverse events and serious adverse 
events 
10.11.2 Development of acute pulmonary edema 
10.11.3 30 days all-cause mortality  
10.11.4 Development of acute kidney injury 
 
 
 
 
 
 
 
 
 
 
 
 
 
11. ADVERSE EVENTS 

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There should be criteria for observing, recording and reporting AE. If AE  would 
endanger a patient, he/she should be excluded from the study and treated 
appropriately. The trial should also be stopped if too many AE are observed. 
 
11.1  Definitions 
11.1.1  Adverse event (AE) 
Any untoward medical occurrence in a subject administered an investigational 
product and which does not necessarily have a causal relationship with 
treatment. An AE can therefore be any unfavourable and unintended sign, 
symptom, laboratory observation or disease temporally associated with the use 
of the investigational product, whether or not related to the investigational 
product. 
 
The following should be reported as AE: 
➢ Treatment emergent symptoms which include: 
• Medical conditions or signs or symptoms that was absent before starting 
study treatment. 
• Medical conditions or signs or symptoms present before starting study 
treatment and worsen (increase severity or frequency) after starting 
study treatment. 
➢ Abnormal laboratory values or tests that induce clinical signs or symptoms 
or require therapy. 
➢ Any adverse experience even if no drug has been administered, for example 
during run in or wash out phase of the study. 
➢ For studies involving a marketed drug in an established indication, AE 
includes significant failure of expected pharmacological or biological action. 
➢ Any doubtful event should be treated as an AE. 
 
 
11.1.2 Unexpected adverse event 
Any adverse event not reported in the safety section of the Investigator's 
Brochure or if the event is of greater frequency, specificity or severity. 
 
 
11.1.3 Serious adverse event (SAE) 
Any adverse event occurring that: 
➢ Results in death 
➢ Is a life threatening adverse experience defined as any adverse event that 
places the subject, in the view of the investigator, at immediate risk of death 
from the reaction as it occurred. Note that this does not include a reaction 
that had it occurred in a more severe form, it would have caused death. 
➢ Results in subject hospitalisation or prolongation of existing hospitalisation. 
 
The following hospitalisations are not considered to be SAEs: 
• Elective treatment for a condition unrelated to study indication or study 
treatment 
• Occur on an emergency outpatient basis and do not result in admission 
(unless fulfilling other criteria in SAE definition) 

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• Part of normal treatment or monitoring of the study indication and are not 
associated with any deterioration in condition. 
• Results in a significant or persistent disability or incapacity defined as 
any event that results in a substantial and/or permanent disruption of the 
subject's ability to carry out normal life functions. 
• Is a congenital anomaly or birth defect 
• Is any instance of overdose, either accidental or intentional (suspected 
or confirmed) 
• Is any other important medical event, based upon appropriate medical 
judgement that may jeopardize the subject or may require medical or 
surgical intervention to prevent or avert one of the outcomes listed 
above. 
 
 
11.2 Detecting and documenting AE 
Information about all AEs, whether volunteered by the patient, discovered by 
investigator questioning or detected through physical examination, laboratory 
test or other means, would be recorded on the Adverse Event Page of the CRF 
and followed up as appropriate. 
 
When eliciting experiences of AE from a subject, ask a standard non-leading 
question like "Do you feel different in any way since starting the new 
treatment/the last visit?" This question will be put to the subject in his/her own 
language at each study visit. 
 
Each AE should be described by: 
a) Nature of AE 
This should be documented in terms of a medical diagnosis(es). When this 
is not possible, the AE should be documented in terms of signs and/or 
symptoms observed by the investigator or reported by the subject. 
 
b) Duration 
Start and end dates 
 
c) Assessment of causality 
The investigator should attempt to explain each AE and assess its 
relationship, if any, to the study treatment. Causality should be assessed 
using the following definitions: 
• Very likely 
- 
The AE follows a reasonable temporal sequence from study 
treatment administration 
- 
Abates upon discontinuation of study treatment 
- 
Reappears on repeated exposure (re-challenge) 
• Probable 
- 
The AE follows a reasonable temporal sequence from study 
treatment administration 
- 
Abates upon discontinuation of study treatment 
- 
Cannot reasonably be explained by known characteristics of the 
subject's clinical state 

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• Possible 
- 
The AE follows a reasonable temporal sequence from study 
treatment administration 
- 
But could have been produced by the subject's clinical state or  other 
mode of therapy administered to the subject 
• Doubtful 
- 
The temporal association between study treatment and AE is such 
that the study treatment is not likely to have any reasonable 
association with the observed event 
• Very unlikely 
- 
The AE is definitely produced by the subject's clinical state or other 
mode of therapy administered to the subject 
 
The degree of certainty with which an AE is attributed to study treatment or 
alternative cause like natural history of disease or concomitant treatment should 
be guided by the following considerations: 
- 
Time relationship between treatment and occurrence of AE 
- 
De-challenge and re-challenge information, if applicable 
- 
Known pharmacology of the drug 
- 
Dose response relationships 
- 
Lack of alternative explanations i.e. no concomitant drug used and 
no other inter-current disease 
- 
Reaction of similar nature being previously observed with this drug 
or class of drug 
- 
Reaction having often been reported in literature for similar drug 
 
d) Severity of AE 
• Mild: awareness of signs or symptoms, but they are easily tolerated 
• Moderate: enough discomfort to cause interference with usual activity 
• Severe: incapacitating, with inability to work or do usual activity 
 
Note that a severe AE is not necessarily serious. The term severe is a 
measure of the intensity while a serious AE is determined based on 
regulatory criteria.  A life threatening AE is an SAE. 
 
 
11.3 Reporting SAE 
Information about all SAE will be recorded on the Serious Adverse Event  Page 
of the CRF. All events documented in the SAE Form must be reported within 
24 hours to Principal Investigator by telephone. The investigator should not wait 
to receive additional information to fully document the SAE before  notifying 
Principal Investigator. A fax SAE form detailing relevant aspects of the SAE in 
question should follow telephone report of SAE. The investigator should also 
comply with the applicable regulatory requirements related to the reporting of 
unexpected serious drug reactions to the regulatory authorities. Where 
applicable, information from relevant medical records and autopsy reports 
should be obtained. 

Clinical Study Protocol Study 
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Any death or congenital abnormality, if brought to the attention of the 
investigator within 6 months after cessation of study treatment, whether 
considered treatment related or not, should be reported to CRC. 
 
Study contact for reporting SAE:  
 
Name: Dr Yeoh Chun Chiat 
Department: Emergency Department 
Tel: 019 - 9316939 
E-mail: ccyeoh@ummc.edu.my 
 
24 hour contact information for physicians on call will be provided to each 
site prior to study initiation. 
 
11.4 Treatment and follow up of AE 
Treatment of any AE is at the sole discretion of the investigator who should 
follow up subjects with AE until the event has resolved or until the condition 
has stabilised. Otherwise appropriate medical care should be arranged for 
the patient. Abnormal tests should be repeated until they return to baseline 
levels or an adequate explanation of the abnormality has been found. Any 
follow up information should be reported to Principal Investigator as soon as 
it becomes available. 
 
➢ Pregnancy 
A female subject must be instructed inform the investigator if she becomes 
pregnant within 90 days after given the study fluids. Monitoring of the subject 
should continue until conclusion of the pregnancy. The investigator should 
report all pregnancies to Principal Investigator within 24 hours of being 
notified of the pregnancy. 
 
The partner should be counselled and followed as described above. 
 
11.5 Safety update 
Should the side effects reported are serious or unexpected and very likely, 
probably or possibly related to the study fluid, the Principal Investigator will 
immediately submit a copy of this information to the IRB/IEC. The IRB/IEC 
will determine if the informed consent requires revision. The investigator 
should also comply with the IRB/IEC procedures for reporting any other 
safety information. 
 
 
 
 
 
 
 
 
 
 
 

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12 
STUDY CONDUCT 
12.1  Study procedures 
Any deviation from the study procedures described below will be 
considered protocol deviation and will be notified to Principal Investigator. 
 
 
12.1.1 Baseline data and laboratory investigation 
Once a patient is recruited as study subject, the following data will be 
collected at baseline: 
➢ Subject's demography: date of birth/age, national registry identification 
card number, sex, race, height (cm) and weight 
➢ Background and medical history which includes any diagnosed medical 
conditions within the previous 12 months, history of medication and 
medical procedures within the previous 30 days of entry into the study. 
➢ Vital signs 
The following vital signs assessments will be performed: 
• Body weight (kg) or estimated body weight (kg) if patient unable to 
stand up and height (cm), no shoes in light clothing 
• Pulse in beats/min, taken at the radial artery over 60 seconds. 
• Blood pressure will be measured with a mercury sphygmomanometer 
at least 2 measurements should be taken with a 2 minute interval 
between measurements. 
• BP should be measured by the same treating physician whenever 
possible and on the same arm. All measurements should be to the 
nearest 2 mmHg. Diastolic BP is determined at Phase V (i.e. 
disappearance of the Korotkoff sound). 
• Capillary refilling time is time taken for color to return to an external 
capillary bed after 5-second pressure is applied to cause blanching. 
 
Blood pressure, pulse rate and capillary refill time will be recorded from 
the initiation of treatment, every 30-minute interval, till 30ml/kg study 
fluids completed or at 2 hours after initiation of study fluid infusion. 
A provisional diagnosis before admission to the ward will be recorded. 
 
12.1.2 Randomisation 
➢ Patients were assigned in a 1:1 ratio by means of randomization using 
online randomizer, http://www.randomiser.com/. 
➢ The code is saved in the randomization log which will only be secured 
by an assigned pharmacist. 
➢ Each time when patient is recruited, a trained pharmacist or senior 
nurse or senior medical officer who is not involved directly in the 
treatment of the subject will open the randomization log and prepare 
the test fluid according to the randomization log. 
➢ The following information will be recorded during randomization: 
• Study ID (assigned during study initiation) 
• Subject's screening status 
• Date of informed consent signed by subject 
• Subject's ID no.  
• Upon successful randomization, the subject will be assigned a 
randomization number and study fluid.  Document the subject's 
ID no.  and randomization no. on the Patient Enrolment Log and 
Patient Identification List. 
    12.1.3 Follow up 

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All subject will be followed up in the ward and the following data will be 
recorded: 
➢ any AE or SAE related to study fluids administration 
➢ BUSEC taken within 48 hours of hospital admission 
➢ any death within 30 days and its cause 
➢ discharge date  
 
12.2 Criteria for stopping subject treatment 
Study fluid may be discontinued depending on the clinician’s judgement 
as followed 
• subject develops acute pulmonary edema  
• subject has clinically improved and does not need further fluid 
resuscitation 
• any situation that the treating physician believes that any further 
infusion of study fluid might worsen the clinical condition of the 
subjects 
If the study fluid needs to be discontinued, the total amount of test 
fluid will be recorded and patient will be excluded from the 
analysis. 
12.3 Sample handling and analysis 
12.3.1 Collection 
Blood gas analysis will be obtained from peripheral veins, central veins 
from subjects, kept in plastic syringes preloaded with measured heparin. 
Blood for electrolytes and creatinine (BUSEC) level will be obtained as 
the same manner and will be kept in the plain tube, labeled. Total blood 
taken for a subject will be 5mls, which includes 0.5mls each for blood gas 
anaylsis(immediately before and after the study fluid is given) and 2mls 
each for BUSEC (immediately before and within 48 hours after the study 
fluid is given). 
 
12.3.2 Labelling of blood samples 
➢ The standard labels provided by hospital Pulau Pinang laboratory 
should be used to label each sample. 
➢ Any hand written additions to the labels should be made using indelible 
ink 
➢ Labels should not be attached to caps. 
 
     12.4  Laboratory analysis 
All blood gas will be analysed as point-of-care using ABL 800 machine in 
the emergency department hospital Pulau Pinang. In the other hand, blood 
for electrolytes and creatinine level will be analysed at the hospital Pulau 
Pinang laboratory. 
 
13. DATA MANAGEMENT 
All the data will be stored in a password encrypted computer which only the 
principle and co-investigators has access to it. The data will be analysed by 
SPSS software using the same computer. Once data analysis is completed, 
the data will be transferred to password encrypted CD and will be kept in the 
high security safe in the Emergency Department, Hospital Pulau Pinang for 
next 5 years and will be destroyed after that. Subjects will not be  given to 
any access to any patient’s information and study data. 
14. STATISTICAL METHODS 

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14.1  Sample size and power considerations 
Sample size is calculated using PS software. The sample size calculation 
assumed the following: α value 0.05, power of 0.95 and standard difference of 
0.05 from previous study. It’s power to detect 0.03 difference in pH between 2 
study fluids. The calculated sample size was 73 patients each arm with total 
sample size 150. 
 
14.2 Randomisation 
Randomization 
is 
made 
using 
online 
randomizer 
(http://www.randomiser.com/). Patient will be randomised to receive either 
Hartmann’s solution or half saline with addition of 75mEq/L sodium 
bicarbonate, ratio is 1:1. 
 
14.3 Analysis 
Data analysis will be performed using the SPSS program. Descriptive 
analysis will be used to describe demographic and disease characteristics 
of the patients. Percentages and frequencies will be used for categorical 
variables while means and standard deviations will be calculated for 
continuous variables. The significance level is set at p-value less than 
0.05.  
The mean difference of blood pH, bicarbonate level and lactate level 
between the two study fluids will be analyzed using Independent T-test 
(normally distributed) or Mann-Whitney Test (non-normally distributed). 
The all-cause mortality at 30 days, development of pulmonary edema and 
incidence of acute kidney injury will between the two study fluids will be 
analyzed using binary logistic regression. The length of stay in hospital 
between the two study fluids used will be analyzed using Independent T-
test (normally distributed) or Mann-Whitney Test (non-normally 
distributed). 
 
 
15 ADMINISTRATIVE MATTERS 
15.1 Notification of regulatory authorities 
All necessary arrangements for the registration and approval of this study 
with the responsible authorities and the disposition of the required data and 
document will be undertaken by the Principal Investigator. 
 
15.2 Study initiation 
Investigators involved in this study must not enrol any patient prior to 
completion of a formal meeting conducted by the Clinical Research Associate 
of CRC. This meeting will include an inventory of study supplies, a detailed 
review of the protocol and CRF, training on study procedures and other 
procedures required of GCP. Investigators who are not GCP certified will 
undergo GCP training during the study. 
 
15.3 Protocol deviation 
Any protocol deviation will be documented by the Principal Investigator with 
rectification as soon as possible. The investigator should be notified 
immediately. With the exception of emergency situations, no changes or 
deviations in the conduct of this protocol will be permitted without the prior 
approval from the Principal Investigator. In the event of any emergency, the 

Clinical Study Protocol Study 
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investigators will institute any medical procedures deemed appropriate. All 
such procedures must be promptly reported to Principal Investigator. 
 
15.4 Study documentation 
The investigator must maintain adequate and accurate records to document 
the conduct of the study and substantiate the study data. These documents 
are Essential Documents and Source Documents. 
 
15.4.1  Essential documents 
These are documents that permit evaluation of the study and the quality 
of the data produced.  The Essential Documents are: 
➢ Signed protocol amendments 
➢ Sample CRFs 
➢ IRB/IEC approval letter, including a dated list of IRB/IEC 
membership and members' affiliation 
➢ Informed consent form 
➢ CV of investigator and co-investigator 
➢ Correspondences with IRB/IEC, sponsor and CRC 
➢ Interim reports to IRB/IEC 
➢ Site signature log 
➢ Monitor visit log 
➢ Screening log 
➢ Other appropriate documents in accordance with GCP  guidelines. 
 
The investigator will maintain an Investigators Study File. This file shall 
be used to facilitate and ensure filing of all relevant and Essential 
Documents during and after the study.  The investigator will be 
responsible for keeping  the Investigator's Study File updated and 
ensuring that all required documents are filed. The file will be inspected 
during monitoring visits. 
 
 
15.4.2 
Source documents 
These are original hospital records, clinical charts, subject screening  
checklist, original laboratory reports, memoranda, pharmacy dispensing 
records, recorded data from automated instruments, transcriptions 
certified after verification as being accurate, microfiches, photographic 
negatives, microfilm, magnetic or electronic media, x-rays, subjects' files, 
and records kept at the pharmacy, at the laboratories and at medico-
legal departments involved in the study. 
 
The investigator must maintain source documents for each patient in the 
study. All information on CRFs must be traceable to these source 
documents: 
➢ Patient identification list 
➢ Curriculum vitae 
➢ Site signature/authorization log 
 
 
 
 
 
 
 
15.5 Patient identification list/Enrolment log 

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The investigator has to maintain a list of all enrolled patients containing the 
full name, date of birth, date of enrolment, and the randomization number. 
The list has to show an unequivocal study identification number. The list will 
be filed in the Investigator's Study File on site. 
 
 
15.6 Curriculum vitae 
The investigator will provide curriculum vitae showing his/her experience in 
the area of the proposed study. These should be filed at CRC as well as in 
the Investigator's Study File on site. 
 
 
15.7 Site signature/authorization log 
The investigator must maintain a Signature Log to document signatures and 
initials of all staff authorized to make entries and/or corrections on CRFs and 
other study related records or documents. The log will be filed in the 
Investigator's Study File. 
 
 
15.8 Monitoring the study 
The investigator agrees to cooperate with any monitor from the IEC to ensure 
that any problems detected in the course of these monitoring visits are 
resolved. 
 
 
15.9 Audits and Inspections 
The investigators should make available the various records of the trial to 
health authority inspectors after appropriate notification. The verification of 
CRFs data will be made by direct inspection of source documents. 
 
15.10 Retention of documents 
The investigator shall arrange for the retention of all study documents and 
records, including subject records, screening log, signed informed consent 
forms and the patient identification list for at least 3 years after completion or 
discontinuation of the study. 
 
If the investigator moves or retires, he/she must nominate someone in writing 
to be responsible for archiving. Archived data may be held in microfiche or 
electronic record, provided a back up exists and a hard copy can be obtained 
from it if required. 
 
If the investigator cannot guarantee this archiving requirement at the study  
site for any or all of the documents, special arrangements must be made with 
the sponsor or CRC to store these in a sealed container(s) outside of the site 
so that they can be returned sealed to the investigator in case of a  regulatory 
audit. Where source documents are required for the continued care of the 
subject, appropriate copies should be made for storage outside of the site. 
 
 
 
 
15.11 Finance 
This is a self-funded study. 

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15.12 Study Termination and Site Closure 
Reasons that may require termination of the study include: 
➢ It becomes apparent that patient enrolment is unsatisfactory with respect  
to quality or quantity. 
➢ Date recording is inaccurate and/or incomplete 
➢ Deliberate violation of the signed protocol 
 
Should Principal Investigator decide to terminate the study, the investigator 
will complete the CRFs as far as possible.  
 
15.13 Confidentially 
Patients’ data are kept strictly confidential by the investigator or any person 
connected with the work and shall not be disclosed to any third party without 
the prior written consent of the principle investigator. 
 
 
15.14 Publication policy 
Any proposed publication or presentation (eg. manuscript, abstract or poster) 
for submission to journal or scientific meeting should be sent to Director 
General of Health at least 45 days prior to submission for manuscripts, and 
at least 21 days prior to submission to publishers for abstracts. 
 
15.15 Anticipated subject accrual and duration of the study 
This study is expected to start in 2017. The projected study timetable for  the 
study is as follows: 
➢ First patient enrolled is expected in 1st Feb 2017 
➢ Last patient enrolled is expected in 31st  Dec  2017 
The planned date of last outcome is 31st Jan 2018. 
These accrual rates are based on reasonable planning expectations. The 
investigator should however continually compare the actual and expected 
accrual rates, and make every effort to ensure that they are as closely 
matched as possible. If the investigator anticipates major problems with 
recruitment, or delay in the expected completion date, he/she should discuss 
this with the CRC staff as early as possible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16 
REFERENCES 
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17 
APPENDICES 
 
➢ Data collection forms 
➢ Patient information sheet (in English) 
➢ Patient information sheet (in Bahasa Malaysia)  
➢ Patient’s informed consent (in English) 
➢ Patient’s informed consent (in Bahasa Malaysia)