The Impact of Systemic pH on Cardiac Function and Clinical Outcome in the Critically Ill Patient
Conditions: Acidosis, Cardiac; Deficiency, Acid Base Disorder
Sponsor: King's College Hospital NHS Trust

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 1 of 39 
 
Observational Protocol Template: KCH/KCL Sponsored Studies 
 
Guidance 
 
This protocol template is for use by KCH/KCL investigators to submit studies for KCH or KCL 
Sponsorship via the KCH Research & Innovation Office.  
 
This template is not applicable for all studies: 
 
 
deemed to be Clinical Studies of Investigational Medicinal Products (CTIMP)  
 
involving new Devices or Devices being used for a new purpose 
 
This template has been developed to include all relevant regulatory, ethics and local policy 
requirements. The template contains all sections recommended by the Health Research Authority 
(HRA) for regulatory review by the HRA and the Research Ethics Committees. 
 
Investigators may use other templates, but must ensure the sufficient level of detail is presented. 
Investigators wishing to do so are encouraged to read through this template. Text marked in black 
must be inserted into these protocols. 
 
 
The R&I Office will review each protocol submitted to ensure key sections and details are included 
before Sponsorship is formally agreed.  
  
Instructions for use 
Not all sections will be relevant for all studies. Each section can be modified or deleted as 
applicable to your type of study.  
 
Instructions and explanatory text are indicated in red and should be removed or replaced in your 
protocol with the appropriate text. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 2 of 39 
 
 
 
 
Short title 
The impact of the pH on cardiac output in the critically ill patient 
 
Full title of trial 
The impact of systemic pH on cardiac function and clinical outcome in the critically ill patient 
 
Sponsor: 
 
King’s College Hospital NHS Foundation Trust (KCH)  
Funder (s): 
There are not funders 
IRAS Reference 
IRAS Project ID: 227870  
 
ISRCTN / Clinicaltrials.gov no:  
 
It is not a trial but I am in the process of registration 
 
Protocol Version: 3rd and Date: 26/03/2018 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 3 of 39 
 
 
 
 
 
KEY ROLES AND RESPONSIBILITIES 
SPONSOR: The sponsor is responsible for ensuring before a study begins that arrangements are in place for the research 
team to access resources and support to deliver the research as proposed and allocate responsibilities for the 
management, monitoring and reporting of the research. The Sponsor also has to be satisfied there is agreement on 
appropriate arrangements to record, report and review significant developments as the research proceeds, and approve 
any modifications to the design.  
 
FUNDER: The funder is the entity that will provide the funds (financial support) for the conduction of the study. Funders 
are expected to provide assistance to any enquiry, audit or investigation related to the funded work. If further 
arrangements have been agreed with the funder, please refer to the funding agreement and insert  
 
CHIEF INVESTIGATOR (CI): The person who takes overall responsibility for the design, conduct and reporting of a study. If 
the study involves researchers at more than once site, the CI takes on the primary responsibility whether or not he/she is 
an investigator at any particular site. 
 
The CI role is to complete and to ensure that all relevant regulatory approvals are in place before the study begins. Ensure 
arrangements are in place for good study conduct, robust monitoring and reporting, including prompt reporting of 
incidents, this includes putting in place adequate training for study staff to conduct the study as per the protocol and 
relevant standards. 
 
The Chief Investigator is responsible for submission of annual reports as required. The Chief Investigator will notify the R&I 
Office of the end of the study, including the reasons for the premature termination. Within one year after the end of study, 
the Chief Investigator will submit a final report with the results, including any publications/abstracts to the REC.  
 
PRINCIPAL INVESTIGATOR (PI):  Individually or as leader of the researchers at a site; ensuring that the study is conducted 
as per the approved study protocol, and report/notify the relevant parties – this includes the CI of any breaches or 
incidents related to the study. 
 
OTHER: add other key personal/entity responsibilities where relevant to the study 
 
DECLARATIONS 
The undersigned confirm that the following protocol has been agreed and accepted and that the 
investigator agrees to conduct the study in compliance with the approved protocol and will adhere 
to the Research Governance Framework 2005 (as amended thereafter), the Trust Data & 
Information Governance policy, Sponsor and other relevant SOPs and applicable Trust policies and 
legal frameworks. 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 4 of 39 
I (investigator) agree to ensure that the confidential information contained in this document will not 
be used for any other purposes other than the evaluation or conduct of this research without the 
prior written consent of the Sponsor. 
I (investigator) also confirm that an honest accurate and transparent account of the study will be 
given; and that any deviations from the study as planned in this protocol will be explained and 
reported accordingly. 
 
Chief Investigator: 
 
Signature:....................................................................................      Date 06/ 03/2018 
Print Name (in full): SANCHO RODRIGUEZ-VILLAR 
Position: Intensive Care Medical Consultant. King´s College NHS Foundation Trust. London, UK. 
 
CONTENTS 
Trial personnel .................................................................................................................................................................. 6 
1 
INTRODUCTION ............................................................................................................................................... 17 
2 
BACKGROUND AND RATIONALE ............................................................................................................. 18 
3 
OBJECTIVES ....................................................................................................................................................... 18 
4 
STUDY DESIGN ................................................................................................................................................. 19 
5 
STUDY SCHEDULE .......................................................................................................................................... 23 
6 
CONSENT ............................................................................................................................................................ 23 
7.1 
Inclusion Criteria ................................................................................................................................... 23 
7.2 
Exclusion Criteria .................................................................................................................................. 23 
7 
RECRUITMENT ................................................................................................................................................. 25 
8 
STATISTICAL METHODS .............................................................................................................................. 25 
9 
PATIENT AND PUBLIC INVOLVEMENT (PPI) ..................................................................................... 29 
10 
FUNDING AND SUPPLY OF EQUIPMENT .............................................................................................. 29 
11 
DATA HANDLING AND MANAGEMENT ................................................................................................. 29 
12 
MATERIAL/SAMPLE STORAGE ................................................................................................................. 29 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 5 of 39 
13 
PEER AND REGULATORY REVIEW .......................................................................................................... 30 
14 
ASSESMENT AND MANAGEMENT OF RISK ......................................................................................... 30 
15 
RECORDING AND REPORTING OF EVENTS AND INCIDENTS ...................................................... 30 
16.1      Definitions of Adverse Events ............................................................................................................. 30 
15.2 
Assessments of Adverse Events .......................................................................................................... 30 
15.3 
Recording adverse events: N/A .......................................................................................................... 32 
15.4 
Procedures for recording and reporting Serious Adverse Events: N/A. NOT APPLICABLE
 
32 
16.5 
Serious Adverse Events that do not require reporting ............................................................... 35 
15.6 
Reporting Urgent Safety Measures ................................................................................................... 35 
15.7 
Protocol deviations and notification of protocol violations ...................................................... 35 
16.8 
Reporting incidents involving a medical device ............................................................................ 35 
15.9 
Trust incidents and near misses. NOT APPLICABLE from the observational study ..... 36 
16 
MONITORING AND AUDITING ................................................................................................................... 36 
17 
TRAINING ........................................................................................................................................................... 36 
18 
INTELLECTUAL PROPERTY: N/A. NOT APPLICABLE ...................................................................... 37 
19 
INDEMNITY ARRANGEMENTS .................................................................................................................. 37 
20 
ARCHIVING ........................................................................................................................................................ 37 
21 
PUBLICATION AND DISSEMINATION POLICY .................................................................................... 39 
22 
REFERENCES .................................................................................................................................................... 39 
23 
APPENDICES ..................................................................................................................................................... 39 
 
 
KEY WORDS 
pH, cardiac contractility, acidosis, cardiac output 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AR 
CAG 
Adverse Reaction 
Confidential Advisory Group 
CI 
Chief Investigator 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 6 of 39 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
GAfREC 
Governance Arrangement for NHS Research Ethics 
HRA 
Health Research Authority 
HTA 
Human Tissue Authority 
ICF 
Informed Consent Form 
ISRCTN 
International Standard Randomised Controlled Studies Number 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
REC 
Research Ethics committee 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure 
TMF 
Trial Master File 
 
 
 
 
 
 
 
Trial personnel 
 
Chief Investigator 
Sancho Rodriguez-Villar 
e-mail:  sancho.villar@nhs.net 
tel:  07860607345 
 
 
 
Sponsor 
 
 
 
Liba Stones 
R&I Manager, King’s College Hospital NHSFT 
161 Denmark Hill, London, SE5 9RS 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 7 of 39 
And 
 
Keith Brennan 
Director of Research Management and Innovation,  
King’s College London, Room 5.23,  
James Clerk Maxwell Building,  
Waterloo Campus, 
 57 Waterloo Road,  
London  SE1 8WA 
 
Statistician (if applicable) 
Dr Juan Arevalo  
e-mail:  fetiche@telefonica.net 
tel:  0034 625 981 199  
 
Head of Department: Dr Georg Auzinger (Critical Care Department at King´s College) 
The team of researches (all of them volunteers, including myself) who will be extracting data 
from medical notes, ICU charts and ICCA will be: 
 
1. Dr Sancho Rodriguez-Villar (Consultant ICU at KINGs) 
2. Dr Ashraf Molokhia (Consultant ICU at Lewisham and Greenwich NHS Trust) 
3. Dr Ahmed Zaki (Consultant ICU at Lewisham and Greenwich NHS Trust) 
4. Dr Paola Eiben (Clinical ICU Fellow) 
5. Dr Charlotte Brathwaite Shirley (Medical ACCS) 
6. Dr Priyakam Chowdhury (ST7 Anaesthesia) 
7. Dr Ana Spataru (ICU Senior Clinical Fellow) 
8. Dr Varsha Ramakrishnan (ICU Clinical Fellow) 
9. Dr Vasile Recea (ICU Clinical Fellow) 
10.Dr Pervez Khan (ICU Senior Clinical Fellow) 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 8 of 39 
11.Dr Bryony Davy (SpR Anaesthesia) 
12.Dr Szilvia Szoke (ICU Clinical Fellow) 
 
 
 
 
 
STUDY SUMMARY 
STUDY OVERVIEW 
Full title 
The impact of systemic pH on cardiac function and clinical outcome in 
the critically ill patient 
Objectives 
Hypothesis 
Titration studies in animals with normal cardiac function show 
that a reduction in blood pH (and presumably that of the 
intracellular and interstitial compartments) from the normal level 
of 7.40 to 7.20 is associated with a rise in cardiac output. 
However, when blood pH is less than 7.20, cardiac output is 
reduced.  Similar studies in humans with or without normal 
cardiac function have not been done, and yet blood pH at which 
aggressive treatment is recommended has been set at 7.20 based 
solely on animal experiments. We hypothesize that a change in 
blood pH in humans will also affect cardiac function, but the level 
of blood pH at which this is observed might be similar or 
different in humans. In addition, the presence or absence of 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 9 of 39 
underlying cardiac disease and the type of acid-base abnormality 
present might modify the response of the heart to changes in 
blood pH. 
 
Goals 
Primary 
1. Assess whether there are significant changes in cardiac 
function associated with changes in blood pH. 
2. Relate the changes in cardiac function to presence or 
absence of underlying cardiac disease. 
Secondary 
3. To establish which factors affected by blood pH have an 
impact on cardiac function. 
4. Study the mortality of patients admitted to the Intensive Care 
Unit (ICU) who had continuous cardiac monitoring at any time 
during their admission and relate it to changes in blood pH. 
 
 
 
 
Type of trial 
It is not a trial 
Trial design and methods 
It is not a trial 
Health condition(s) or 
problem(s) studied 
It is not a trial 
Target sample size 
Taking into account that the primary objective of the study is to 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 10 of 39 
analyze the relationship between the quantitative variables: change 
in pH and change in Cardiac Contractility, assuming an alpha risk of 
5% (95% confidence level), a 20% beta risk (power of 80%) and a 
minimum ratio that has an estimated clinical significance with a 
correlation coefficient of 1.5, a bilateral estimate of sample size of 
346 subjects is obtained. Assuming a 5% loss (17 individuals) 
during the study a total of 363 cases would be necessary. 
 
Trial design and methods 
It is not a trial 
Trial duration per 
participant: 
It is not a trial 
Main inclusion/exclusion 
criteria: 
EXCLUSION CRITERIA 
 
Atrial or ventricular 
arrhythmia:  you need a stable pulse 
to measure the contour. 
 
Aortic, mitral or tricuspid valve 
insufficiency. In the case of valve 
insufficiency the valve does not close 
correctly. Therefore, the 
thermodilution curve is affected by 
indicator regurgitation, resulting in a 
prolonged indicator decay time. 
 
Intra-Aortic Balloon pump:  once 
again, the pulse contour is all wrong; 
but you can still get thermodilution 
cardiac output measurements.  
 
Aortic aneurysm: the contour will be 
bizarre because the arterial 
compliance is going to be weird, with 
the aortic aneurysm acting as a 
damping system by absorbing all the 
pressure wave. 
 
Extracorporeal circuit: when you 
are on bypass, there is no real arterial 
waveform  
 
Pneumonectomy: PiCCO relies on 
there being a relatively normal 
pulmonary vasculature. 
 
Massive pulmonary embolism: as 
above; it is essentially a   
pneumonectomy by embolism.  
 
Intracardiac shunt:  the PA catheter 
will also give an inaccurate 
thermodilution reading. 
 
Less than a minimal tidal volume 6-

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 11 of 39 
8mL/kg  
 
NON-positive pressure ventilated 
patients:  
 Why does Stroke Volume 
Variation only apply to 
positive pressure ventilated 
patients? It still applies in 
spontaneously breathing 
patients; however it is a 
poorer predictor of fluid 
responsiveness.  
 Why? The sensitivity is 
decreased: its only 63%. The 
spontaneous breathing efforts 
draw a smaller tidal volume, 
and from such minor changes 
in thoracic pressure there 
would insufficient change in 
ventricle loading; so there 
may still be changes to stroke 
volume, but they would be 
tiny and difficult to measure. 
 - If there is profound 
hypovolemia, the IVC can 
collapse on inspiration. 
Obviously this decreases 
preload, and confuses your 
SVV. You cannot predict fluid 
responsiveness this way, 
because you never get an 
accurate impression of 
preload.  
 - In spontaneous respiration, 
inspiraton increases the 
right venticular preload, 
which means the right 
ventricular filling is likely still 
appear adequate even if there 
is some hypovolemia. In spite 
of low overall volume, the 
right ventricular preload 
remains adequate, and thus at 
least one of the ventricles is 
likely to be operating in the 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 12 of 39 
preload-independent straight 
part of the Frank-Starling 
curve  
 Severe obesity: In obese patients, 
Extravascular Lung Water Index 
(EVLWI) is underestimated 
because it is related to the body 
weight. 
 
Statistical methodology 
and analysis: 
Statistical methods 
The description of quantitative variables is carried out with 
central tendency and dispersion indices, whether based on values 
(mean and standard deviation) or on ordinations (median and 
interquartile range) according to whether they meet normality or 
not, respectively. Its graphic representation is done with 
Histograms and Cash Diagrams. The description of categorical 
variables is performed with absolute and relative frequencies in 
percentages. Its graphic representation is done with bar charts. 
 
The relationship between categorical variables is analyzed by 
comparing proportions with the Pearson Chi-square test, provided 
that there are less than 20% of squares in the contingency table 
with expected frequencies less than 5. In the case that there is 
more 20% of squares with expected frequencies less than 5, the 
Fisher's exact test is used bilaterally. 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 13 of 39 
The magnitude of the effect of the relationship between two 
binary variables has been analyzed with the Ratios of proportions 
or Relative Risk and with the Odds Ratio. 
 
The relationship between a binary exposure variable and a 
quantitative response is analyzed with the Student-Fisher t test for 
independent samples if the normality condition is met. According 
to whether or not the equality of variances are met, the Student-
Fisher t test is used for independent groups for homogeneous 
variances or for non-homogeneous variances, respectively. In 
case of not fulfilling the condition of normality, the comparison 
of two means is made with the non-parametric Mann-Whitney U 
test. 
 
The comparison between a polytomic predictor and a quantitative 
response is made through the analysis of variance (ANOVA) in 
the case of meeting the conditions of normality and homogeneity 
of variances. If any of these conditions is not met, it is done with 
the non-parametric H test of Kruskal-Wallis. If the polytomic 
predictor is ordinal, the ANOVA trend test or the non-parametric 
Jonckheere-Terpstra trend test is also used, depending on whether 
normality is met or not, respectively. 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 14 of 39 
 
The relationship between two independent quantitative variables 
is evaluated with the correlation coefficient r of Pearson if 
normality is met, or with the nonparametric correlation coefficient 
rho of Spearman if normality is not met. Its graphic representation 
is made with the scatter diagrams or points. 
 
Normality is assessed with the Kolmogorov-Smirnov test with the 
Lilliefors significance correction for large samples, or with the 
Shapiro-Wilks test for small samples. The equality of variances is 
analyzed with the Levene variance homogeneity test. 
 
The relationship between two related quantitative variables is 
performed using the Student-Fisher t-test for related samples in 
case the normality condition is met. Otherwise, the non-
parametric Wilcoxon T test is used. The relationship between two 
paired categorical variables is performed by the McNemar 
symmetry test. 
 
The relationship between a continuous quantitative response and 
one or several predictors, whether binary, polytomic or 
quantitative, is done with Simple or Multiple Linear Regression 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 15 of 39 
respectively. 
The polytomous predictors variables are introduced in the Linear 
Regression models broken down into binary indicator variables 
coded with respect to the first reference category. 
 
An estimative multivariate linear regression model of the effect of 
the predictor Change of pH (between the lowest and highest pH) 
on the response Change in cardiac output (corresponding to the 
moments between the lowest and the highest pH) has been 
performed. The possible role as confounding factors of several 
variables on this relationship has been evaluated. A predictive 
multivariate model of linear regression has been performed to 
evaluate the factors that intervene in the Cardiac Contractility. 
 
Both the predictive and the estimative models have been carried 
out with the manual backward step procedure using the criterion 
of decreasing statistical significance to establish the order to 
evaluate the withdrawal or permanence of each predictor. 
 
In the multivariate predictive linear regression model, the 
criterion of statistical significance was used to decide the 
maintenance or withdrawal of the predictors in each step. They 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 16 of 39 
remain in the model if they are significant and are removed from 
the model if they are not significant.  
In the multivariate models of linear regression, the criterion of 
clinical significance has been used to decide on the maintenance 
or withdrawal of the predictors in each step. They remain in the 
model if they produce a change greater than 10% in the 
coefficient of the predictor of interest (presence of confounding 
bias) and withdraw if the change is less than 10% (absence of 
confounding bias).  
 
The conditions of application of the simple or multiple linear 
regression (linearity, independence, normality and equality of 
variances) are evaluated by analysing the residuals.  
 
Values of P <0.05 are considered significant. The statistical 
treatment has been performed the statistical package SPSS, 
version 18 (SPSS Inc, Chicago, IL, USA). 
 
 
 
STUDY TIMELINES 
Study Duration/length 
Approximately 6 months 
Expected Start Date 
April 2018  
 
End of Study definition and 
Expected on November 2018 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 17 of 39 
anticipated date 
Key Study milestones  
 
March study submission 
April 2018 start of data collection 
October –November data analysis 
 
STORAGE of SAMPLES             No applicable 
(if applicable)        
Human tissue samples 
No applicable 
Data collected / Storage 
Observational data will be completely anonymous before digital 
storage and sending for analysis. Previous to that, it will be collected 
on paper form which will be encrypted coded. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 INTRODUCTION 
 
Why?  
We would like to perform an analysis of the relationship between systemic pH and cardiac 
function and clinical outcome in critically ill patients in patients hospitalized the Intensive Care 
Unit. 
 
How is it of relevance and importance to patients and public?  
Studying this subject we could provide important information about the impact of systemic pH 
on cardiac function and clinical outcome in seriously ill patients and enable the clinician to 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 18 of 39 
understand the best treatment of these patients. Patients will be studied who had cardiac 
monitoring during their ICU admission and an acid-base metabolic disorder. We exclude those 
patients with cardiac history or who presented an acute coronary syndrome during ICU 
admission. 
 
IT IS NOT A THERAPEUTIC STUDY. ONLY OBSERVATIONAL. NO INTERVENTIONS. 
 
Where?  
In seven different ICU´s between King´s College NHS Foundation Hospital and Lewisham and 
Greenwich NHS Trust  
 
How?  
The study will take approximately six month to collect prospectively data from each unit. The 
data will be extracted from the medical notes and ICU charts. No active involvement with 
participants. 
2 BACKGROUND AND RATIONALE 
3 OBJECTIVES 
Goals 
Primary 
1. Assess whether there are significant changes in cardiac function associated with 
changes in blood pH. 
2. Relate the changes in cardiac function to presence or absence of underlying cardiac 
disease. 
Secondary 
3. To establish which factors affected by blood pH have an impact on cardiac function. 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 19 of 39 
4. Study the mortality of patients admitted to the Intensive Care Unit (ICU) who had 
continuous cardiac monitoring at any time during their admission and relate it to changes in 
blood pH. 
 
4 STUDY DESIGN 
 
Study population and groups: those patients on haemodynamic monitoring in ICU (PiCCO 
monitoring) 
 
 Calculation of the sample size: 
Taking into account that the primary objective of the study is to analyze the relationship 
between the quantitative variables: change in pH and change in Cardiac Contractility, 
assuming an alpha risk of 5% (95% confidence level), a 20% beta risk (power of 80%) and a 
minimum ratio that has an estimated clinical significance with a correlation coefficient of 1.5, 
a bilateral estimate of sample size of 346 subjects is obtained. Assuming a 5% loss (17 
individuals) during the study a total of 363 cases would be necessary. 
 Statistical methods: 
The description of quantitative variables is carried out with central tendency and dispersion 
indices, whether based on values (mean and standard deviation) or on ordinations (median 
and interquartile range) according to whether they meet normality or not, respectively. Its 
graphic representation is done with Histograms and Cash Diagrams. The description of 
categorical variables is performed with absolute and relative frequencies in percentages. Its 
graphic representation is done with bar charts. 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 20 of 39 
The relationship between categorical variables is analyzed by comparing proportions with the 
Pearson Chi-square test, provided that there are less than 20% of squares in the contingency 
table with expected frequencies less than 5. In the case that there is more 20% of squares with 
expected frequencies less than 5, the Fisher's exact test is used bilaterally. 
 
The magnitude of the effect of the relationship between two binary variables has been 
analyzed with the Ratios of proportions or Relative Risk and with the Odds Ratio. 
 
The relationship between a binary exposure variable and a quantitative response is analyzed 
with the Student-Fisher t test for independent samples if the normality condition is met. 
According to whether or not the equality of variances are met, the Student-Fisher t test is 
used for independent groups for homogeneous variances or for non-homogeneous variances, 
respectively. In case of not fulfilling the condition of normality, the comparison of two means 
is made with the non-parametric Mann-Whitney U test. 
 
The comparison between a polytomic predictor and a quantitative response is made through 
the analysis of variance (ANOVA) in the case of meeting the conditions of normality and 
homogeneity of variances. If any of these conditions is not met, it is done with the non-
parametric H test of Kruskal-Wallis. If the polytomic predictor is ordinal, the ANOVA trend 
test or the non-parametric Jonckheere-Terpstra trend test is also used, depending on whether 
normality is met or not, respectively. 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 21 of 39 
The relationship between two independent quantitative variables is evaluated with the 
correlation coefficient r of Pearson if normality is met, or with the nonparametric correlation 
coefficient rho of Spearman if normality is not met. Its graphic representation is made with 
the scatter diagrams or points. 
 
Normality is assessed with the Kolmogorov-Smirnov test with the Lilliefors significance 
correction for large samples, or with the Shapiro-Wilks test for small samples. The equality 
of variances is analyzed with the Levene variance homogeneity test. 
 
The relationship between two related quantitative variables is performed using the Student-
Fisher t-test for related samples in case the normality condition is met. Otherwise, the non-
parametric Wilcoxon T test is used. The relationship between two paired categorical variables 
is performed by the McNemar symmetry test. 
 
The relationship between a continuous quantitative response and one or several predictors, 
whether binary, polytomic or quantitative, is done with Simple or Multiple Linear Regression 
respectively. 
The polytomous predictors variables are introduced in the Linear Regression models broken 
down into binary indicator variables coded with respect to the first reference category. 
 
An estimative multivariate linear regression model of the effect of the predictor Change of 
pH (between the lowest and highest pH) on the response Change in cardiac output 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 22 of 39 
(corresponding to the moments between the lowest and the highest pH) has been performed. 
The possible role as confounding factors of several variables on this relationship has been 
evaluated. A predictive multivariate model of linear regression has been performed to 
evaluate the factors that intervene in the Cardiac Contractility. 
 
Both the predictive and the estimative models have been carried out with the manual 
backward step procedure using the criterion of decreasing statistical significance to establish 
the order to evaluate the withdrawal or permanence of each predictor. 
 
In the multivariate predictive linear regression model, the criterion of statistical significance 
was used to decide the maintenance or withdrawal of the predictors in each step. They remain 
in the model if they are significant and are removed from the model if they are not 
significant.  
In the multivariate models of linear regression, the criterion of clinical significance has been 
used to decide on the maintenance or withdrawal of the predictors in each step. They remain 
in the model if they produce a change greater than 10% in the coefficient of the predictor of 
interest (presence of confounding bias) and withdraw if the change is less than 10% (absence 
of confounding bias).  
 
The conditions of application of the simple or multiple linear regression (linearity, 
independence, normality and equality of variances) are evaluated by analysing the residuals.  
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 23 of 39 
Values of P <0.05 are considered significant. The statistical treatment has been performed the 
statistical package SPSS, version 18 (SPSS Inc, Chicago, IL, USA). 
 
 
 
 
 
5 STUDY SCHEDULE 
Approximately:  
 
April 2018: Start collecting data from patient already in the ICU with the inclusion criteria. 
 
April 2018- September 18 approximately until reach the minimum number of 360 patients 
 
October-November 18 data analysis  
 
6 CONSENT 
 
We believe need for individual patient or personal/legal rep consent should be waived. The 
following aspects, needed for seeking informed consent to access patients’ records, are 
considered disproportionate to this observational study: the difficulty, or even impossibility, of 
locating and contacting all patients; the high costs and effort needed; the risk of bias (Al-Shahi et 
al., 2005; McKinney et al., 2005; Jousilahti et al., 2005); and the very low risk of breaching 
individuals’ privacy. In addition, strict and thorough strategies will be put in place data 
protection and confidentiality. Moreover, the British public has been found to be highly 
supportive of the use of personal medical data in non-commercial medical research which “has 
no effect on the individuals being studied and has been approved by an accredited research 
ethics committee” (Peto et al., 2004, p. 1030). Therefore, consent will not sought.  
ELIGIBILITY CRITERIA 
7.1 Inclusion Criteria 
 
Over 16 years old- 65 years old 
 
On cardiac monitoring (PiCCO device) 
7.2 Exclusion Criteria 
 
EXCLUSION CRITERIA 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 24 of 39 
 
Atrial or ventricular arrhythmia:  you need a stable pulse to 
measure the contour. 
 
Aortic, mitral or tricuspid valve insufficiency. In the case of 
valve insufficiency the valve does not close correctly. Therefore, 
the thermodilution curve is affected by indicator regurgitation, 
resulting in a prolonged indicator decay time. 
 
Intra-Aortic Balloon pump:  once again, the pulse contour is all 
wrong; but you can still get thermodilution cardiac output 
measurements.  
 
Aortic aneurysm: the contour will be bizarre because the arterial 
compliance is going to be weird, with the aortic aneurysm acting 
as a damping system by absorbing all the pressure wave. 
 
Extracorporeal circuit: when you are on bypass, there is no real 
arterial waveform  
 
Pneumonectomy: PiCCO relies on there being a relatively 
normal pulmonary vasculature. 
 
Massive pulmonary embolism: as above; it is essentially a   
pneumonectomy by embolism.  
 
Intracardiac shunt:  the PA catheter will also give an inaccurate 
thermodilution reading. 
 
Less than a minimal tidal volume 6-8mL/kg  
 
NON-positive pressure ventilated patients:  
 Why does Stroke Volume Variation only apply to 
positive pressure ventilated patients? It still applies in 
spontaneously breathing patients; however it is a poorer 
predictor of fluid responsiveness.  
 Why? The sensitivity is decreased: its only 63%. The 
spontaneous breathing efforts draw a smaller tidal 
volume, and from such minor changes in thoracic 
pressure there would insufficient change in ventricle 
loading; so there may still be changes to stroke volume, 
but they would be tiny and difficult to measure. 
 - If there is profound hypovolemia, the IVC can 
collapse on inspiration. Obviously this decreases 
preload, and confuses your SVV. You cannot predict fluid 
responsiveness this way, because you never get an 
accurate impression of preload.  
 - In spontaneous respiration, inspiraton increases the 
right venticular preload, which means the right 
ventricular filling is likely still appear adequate even if 
there is some hypovolemia. In spite of low overall 
volume, the right ventricular preload remains adequate, 
and thus at least one of the ventricles is likely to be 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 25 of 39 
operating in the preload-independent straight part of the 
Frank-Starling curve  
 Severe obesity: In obese patients, Extravascular Lung Water 
Index (EVLWI) is underestimated because it is related to the 
body weight. 
 
7 RECRUITMENT 
The recruitment section may include: 
 
 
Method for identifying and recruiting participants for the study: mechanical screening. It will 
be done daily by researcher in each ICU. Those patient on cardiac monitoring (PiCCO device). 
 
Who will identify and approach participants for consent: Not needed 
8 STATISTICAL METHODS 
The description of quantitative variables is carried out with central tendency and dispersion 
indices, whether based on values (mean and standard deviation) or on ordinations (median 
and interquartile range) according to whether they meet normality or not, respectively. Its 
graphic representation is done with Histograms and Cash Diagrams. The description of 
categorical variables is performed with absolute and relative frequencies in percentages. Its 
graphic representation is done with bar charts. 
 
The relationship between categorical variables is analyzed by comparing proportions with the 
Pearson Chi-square test, provided that there are less than 20% of squares in the contingency 
table with expected frequencies less than 5. In the case that there is more 20% of squares with 
expected frequencies less than 5, the Fisher's exact test is used bilaterally. 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 26 of 39 
The magnitude of the effect of the relationship between two binary variables has been 
analyzed with the Ratios of proportions or Relative Risk and with the Odds Ratio. 
 
The relationship between a binary exposure variable and a quantitative response is analyzed 
with the Student-Fisher t test for independent samples if the normality condition is met. 
According to whether or not the equality of variances are met, the Student-Fisher t test is 
used for independent groups for homogeneous variances or for non-homogeneous variances, 
respectively. In case of not fulfilling the condition of normality, the comparison of two means 
is made with the non-parametric Mann-Whitney U test. 
 
The comparison between a polytomic predictor and a quantitative response is made through 
the analysis of variance (ANOVA) in the case of meeting the conditions of normality and 
homogeneity of variances. If any of these conditions is not met, it is done with the non-
parametric H test of Kruskal-Wallis. If the polytomic predictor is ordinal, the ANOVA trend 
test or the non-parametric Jonckheere-Terpstra trend test is also used, depending on whether 
normality is met or not, respectively. 
 
The relationship between two independent quantitative variables is evaluated with the 
correlation coefficient r of Pearson if normality is met, or with the nonparametric correlation 
coefficient rho of Spearman if normality is not met. Its graphic representation is made with 
the scatter diagrams or points. 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 27 of 39 
Normality is assessed with the Kolmogorov-Smirnov test with the Lilliefors significance 
correction for large samples, or with the Shapiro-Wilks test for small samples. The equality 
of variances is analyzed with the Levene variance homogeneity test. 
 
The relationship between two related quantitative variables is performed using the Student-
Fisher t-test for related samples in case the normality condition is met. Otherwise, the non-
parametric Wilcoxon T test is used. The relationship between two paired categorical variables 
is performed by the McNemar symmetry test. 
 
The relationship between a continuous quantitative response and one or several predictors, 
whether binary, polytomic or quantitative, is done with Simple or Multiple Linear Regression 
respectively. 
The polytomous predictors variables are introduced in the Linear Regression models broken 
down into binary indicator variables coded with respect to the first reference category. 
 
An estimative multivariate linear regression model of the effect of the predictor Change of 
pH (between the lowest and highest pH) on the response Change in cardiac output 
(corresponding to the moments between the lowest and the highest pH) has been performed. 
The possible role as confounding factors of several variables on this relationship has been 
evaluated. A predictive multivariate model of linear regression has been performed to 
evaluate the factors that intervene in the Cardiac Contractility. 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 28 of 39 
Both the predictive and the estimative models have been carried out with the manual 
backward step procedure using the criterion of decreasing statistical significance to establish 
the order to evaluate the withdrawal or permanence of each predictor. 
 
In the multivariate predictive linear regression model, the criterion of statistical significance 
was used to decide the maintenance or withdrawal of the predictors in each step. They remain 
in the model if they are significant and are removed from the model if they are not 
significant.  
In the multivariate models of linear regression, the criterion of clinical significance has been 
used to decide on the maintenance or withdrawal of the predictors in each step. They remain 
in the model if they produce a change greater than 10% in the coefficient of the predictor of 
interest (presence of confounding bias) and withdraw if the change is less than 10% (absence 
of confounding bias).  
 
The conditions of application of the simple or multiple linear regression (linearity, 
independence, normality and equality of variances) are evaluated by analysing the residuals.  
 
Values of P <0.05 are considered significant. The statistical treatment has been performed the 
statistical package SPSS, version 18 (SPSS Inc, Chicago, IL, USA). 
 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 29 of 39 
9 PATIENT AND PUBLIC INVOLVEMENT (PPI) 
 
The impact of changes in acidity on clinical outcome and cardiac function has been examined in 
small numbers of patients in the past. However, its relevance to the monitoring and treatment of 
larger number of patients is unclear. This study should provide important information using a 
large cohort of patients. 
10 FUNDING AND SUPPLY OF EQUIPMENT  
The study funding has been reviewed by the KCH R&I Office, and deemed sufficient to cover the 
requirements of the study.  
 
THIS STUDY IS NOT FUNDED 
11 DATA HANDLING AND MANAGEMENT 
Where data will be recorded: initially on paper with a reference code for each patient. On 
enrolment the patient is given a unique study ID. This usually has a numeric code for the site 
as well as a sequential number for patients e.g 23-001, 23-002 etc. the case report forms 
(data collection forms) only have study ID on. There is no patient ID at all on the CRF, but we 
have an enrolment log- just a list of name, hospital number and study ID.  
12 MATERIAL/SAMPLE STORAGE  
There is usually a copy of this in the site file and on our network drive. This is only accessible 
by appropriate hospital staff and outside researchers only if patient consents. Therefore 
research team knows who the number relates to and could trace back if necessary but no-
one else. This is why we refer to an enrolment log in the IRAS form because we need some 
way of linking patients to data. 
 
 
If samples will be stored for future use (and the details): data will be store for about six 
months. There is usually a copy of this in the site file and on our network drive. 
 
Measures for the processing, control and safe storage of samples: no tissue samples. 
 
Details of data controller/custodian. It will be Chief investigator , myself (Sancho Rodriguez-
Villar) 
 
NOT APPLICABLE :In the study, will be collected from patients in accordance with the patient 
consent form and patient information sheet and shall include all tissue samples or other biological 
materials and any derivatives, portions, progeny or improvements as well as all patient information 
and documentation supplied in relation to them.  Samples will be processed, stored and disposed in 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 30 of 39 
accordance with all applicable legal and regulatory requirements, including the Human Tissue Act 
2004 and any amendments thereafter.  
13 PEER AND REGULATORY REVIEW 
The study has been peer reviewed in accordance with the requirements outlined by KCH R&I.  
 
Choose either (having discussed with the KCH R&I Office): 
 
This study has been peer reviewed within KCH/KCL, by an independent and relevant peer 
reviewer/committee (amend as required) on (insert date). The Sponsor has accepted these 
reviews as adequate evidence of peer review.  
 
14 ASSESMENT AND MANAGEMENT OF RISK 
No applicable 
15 RECORDING AND REPORTING OF EVENTS AND INCIDENTS 
16.1      Definitions of Adverse Events  
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or study participant, 
which does not necessarily have a causal relationship with the 
procedure involved.  
Serious Adverse Event 
(SAE). 
Any adverse event that: 
 
results in death, 
 
is life-threatening*, 
 
requires hospitalisation or prolongation of existing 
hospitalisation**, 
 
results in persistent or significant disability or incapacity, or 
 
consists of a congenital anomaly or birth defect 
*A life- threatening event, this refers to an event in which the participant was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 
** Hospitalisation is defined as an in-patient admission, regardless of length of stay. 
Hospitalisation for pre-existing conditions, including elective procedures do not constitute an SAE. 
15.2 
Assessments of Adverse Events  
Each adverse event will be assessed for severity, causality, seriousness and expectedness as 
described below. 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 31 of 39 
16.2.1    Severity: NOT APPLICABLE 
The generic categories below are given for use as a guide. You may have a more specific scale that 
you want to use related to the disease (e.g. CTCAE criteria). 
Category 
Definition 
Mild 
The adverse event does not interfere with the participant’s daily routine, and does 
not require further procedure; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the participant’s routine, or 
requires further  procedure, but is not damaging to health; it causes moderate 
discomfort 
Severe 
The adverse event results in alteration, discomfort or disability which is clearly 
damaging to health 
 
16.2.2     Causality: N/A. NOT APPLICABLE 
The assessment of relationship of adverse events to the procedure is a clinical decision based on all 
available information at the time of the completion of the case report form.   
If a differentiated causality assessment which includes other factors in the study is deemed 
appropriate, please add/amend the following wording to specify: 
It is of particular importance in this study to capture events related to the product application 
procedure (specify e.g. surgery) / product failure / mandatory concomitant medications (specify e.g. 
conditioning chemotherapy). The assessment of relationship of an adverse event to this/these 
additional safety issue(s) will also be carried out as part of the study.  
The differentiated causality assessments will be captured in the study specific CRF/AE Log and/or 
SAE form (amend as required).  
The following categories will be used to define the causality of the adverse event: 
Category 
Definition 
Definitely: 
There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
Probably: 
There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 32 of 39 
Possibly 
There is some evidence to suggest a causal relationship (e.g. the event occurred 
within a reasonable time after administration of the study procedure). However, 
the influence of other factors may have contributed to the event (e.g. the 
participant’s clinical condition, other concomitant events). 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. the event did 
not occur within a reasonable time after administration of the study procedure). 
There is another reasonable explanation for the event (e.g. the participant’s 
clinical condition). 
Not related 
There is no evidence of any causal relationship. 
Not Assessable 
Unable to assess on information available. 
 
16.2.3   Expectedness: N/A. NOT APPLICABLE from the observational study 
Category 
Definition 
Unexpected 
An adverse event which is not consistent with the information about the procedure 
listed in the manual of operation or clearly defined in this protocol. 
* this includes listed events that are more frequently reported or more severe than previously 
reported 
15.3 Recording adverse events: N/A 
 
NOT APPLICABLE. COLLECTION OF DATA ONLY 
15.4 Procedures for recording and reporting Serious Adverse Events: N/A. NOT 
APPLICABLE 
All serious adverse events will be recorded in the medical records and the CRF, and the sponsor’s AE 
log. All SAEs (except those specified in section 16.5 as not requiring reporting to the Sponsor) must 
be recorded on a serious adverse event (SAE) form. The CI/PI or designated individual will complete 
an SAE form and the form will be preferably emailed to the Sponsor within 5 working days of 
becoming aware of the event. The Chief or Principal Investigator will respond to any SAE queries 
raised by the sponsor as soon as possible.  
Where the event is unexpected and thought to be related to the procedure this must be reported by 
the Investigator to the Health Research Authority within 15 days. 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome 
in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 33 of 39 
 

 
 
 
Full title of the research: The impact of systemic pH on cardiac function and clinical outcome in the critically ill patient. 
  
IRAS Project ID: 227870 
 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 34 of 39 
Flow Chart for SAE reporting  
 
AE occurs 
Assign Severity Grade 
Was the event Serious? 
Was the event an Other 
Notifiable event?  
See section 16.5 for notifiable 
events which should also be 
reported as serious 
No 
No 
Yes 
Yes 
Yes 
No 
Submit SAE form to Sponsor within 5 working days 
Record in medical records,  
And CRF in accordance with the protocol  
 
Record in medical records 
and CRF (if applicable) 
Is the event specified as an adverse event which does not require immediate reporting as an SAE?  
See section 16.5.  
Record in medical records, CRF (and AE Log if 
required)  
Complete an SAE report form 

Short Title, Sponsor Ref, Protocol Version and Date 
35 
 
16.5 Serious Adverse Events that do not require reporting  
It is an observational study. We do not expect any incident. There are not interventions at 
all. If a SAE occurs (from PiCCO monitoring use) will report to the Clinician Consultant in 
charge who is at the end the final responsible of the patient and the responsible of putting 
the PiCCO monitoring on the patient. 
15.6 Reporting Urgent Safety Measures  
If any urgent safety measures are taken the CI/ PI shall immediately and in any event no later than 3 
days from the date the measures are taken, give written notice to the relevant REC and Sponsor of 
the measures taken and the circumstances giving rise to those measures. 
15.7 Protocol deviations and notification of protocol violations 
A deviation is usually an unintended departure from the expected conduct of the study 
protocol/SOPs, which does not need to be reported to the sponsor.   The CI will monitor protocol 
deviations. 
 
 A protocol violation is a breach which is likely to effect to a significant degree – 
(a) the safety or physical or mental integrity of the participants of the study; or 
(b) the scientific value of the study. 
The CI and sponsor will be notified immediately of any case where the above definition applies 
during the study conduct phase.   
16.8 Reporting incidents involving a medical device 
Any adverse incident involving a medical device should be reported to the manufacturer of the 
device.  
This is especially important where the incident has led to or, was it to occur again could lead to an 
event classified as serious (see section 9.1 for definition of SAE). Other minor safety or quality 
problems should be reported along with incidents that appear to be caused by human error.  
All adverse incidents must be reported by the Clinician Consultant responsible of the patient. The 
study is only observational and there are not interventions or decisions involving the use of the 
PiCCO device. That decision will be made by the Clinical Consultant in charge in the ICU therefore 
incidents should be reported as soon as possible (usually within 24 hours) as per protocol in the 
Trust. 
Adverse incidents related to a medical device can be reported directly to the MHRA via the online 
system (www.mhra.gov.uk). Alternative contact details: Medicines & Healthcare products 
Regulatory Agency Adverse Incident Centre (Tel: 020 7084 3080; Fax 020 7084 3109). 
Local trust reporting procedures may also need to be followed. It is the responsibility of the PI and 
study site team to ensure they are aware of any specific local requirements for reporting device 
incidents.  

Short Title, Sponsor Ref, Protocol Version and Date 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 36 of 39 
15.9 Trust incidents and near misses. NOT APPLICABLE from the observational 
study 
An incident or near miss is any unintended or unexpected event that could have or did lead to harm, 
loss or damage that contains one or more of the following components: 
a. It is an accident or other incident which results in injury or ill health. 
b. It is contrary to specified or expected standard of patient care or service. 
c. It places patients, staff members, visitors, contractors or members of the public at 
unnecessary risk. 
d. It puts the Trust in an adverse position with potential loss of reputation. 
e. It puts Trust property or assets in an adverse position or at risk. 
Incidents and near misses must be reported to the Trust through DATIX as soon as the individual 
becomes aware of them. 
A reportable incident is any unintended or unexpected event that could have or did lead to harm, 
loss or damage that contains one or more of the following components: 
 
a) It is an accident or other incident which results in injury or ill health. 
b) It is contrary to specified or expected standard of patient care or service. 
c) It places patients, staff members, visitors, contractors or members of the public at 
unnecessary risk. 
d) It puts the Trust in an adverse position with potential loss of reputation. 
e) It puts Trust property or assets in an adverse position or at risk of loss or damage. 
16 MONITORING AND AUDITING 
The Chief Investigator will ensure there are adequate quality and number of monitoring activities 
conducted by the study team. This will include adherence to the protocol, procedures for consenting 
and ensure adequate data quality.  
 
The Chief Investigator will inform the sponsor should he/she have concerns which have arisen from 
monitoring activities, and/or if there are problems with oversight/monitoring procedures. 
 
 
  
17 TRAINING 
The Chief Investigator will review and provide assurances of the training and experience of all staff 
working on this study.  Appropriate training records will be maintained in the study files 
 
The training section may also include: 
 
Specific training requirements for staff working on the project: NOT APPLICABLE 
 
Specific qualifications and experience required of staff on the project: SENIOR ICU STAFF 
 
Identifying if training may require a renewal at any point throughout the study: NOT 
APPLICABLE 

Short Title, Sponsor Ref, Protocol Version and Date 
 
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18 INTELLECTUAL PROPERTY: N/A. NOT APPLICABLE 
19 INDEMNITY ARRANGEMENTS 
 
 
KCH will provide NHS indemnity cover for negligent harm, as appropriate and is not in the position to 
indemnify for non-negligent harm. NHS indemnity arrangements do not extend to non-negligent 
harm and NHS bodies cannot purchase commercial insurance for this purpose; it cannot give 
advance undertaking to pay compensation when there is no negligence attributable to their 
vicarious liability. The Trust will only extend NHS indemnity cover for negligent harm to its 
employees, both substantive and honorary, conducting research studies that have been approved by 
the R&D Department. The Trust cannot accept liability for any activity that has not been properly 
registered and Trust approved. Potential claims should be reported immediately to the Joint 
Research Office. 
 
20 ARCHIVING 
 
Date of birth 
 
Sex (M/F) 
 
Hospital ADMISSION date 
 
ICU ADMISSION date 
 Unplanned/emergency admission. 
 Planned /elective admission. 
 
ICU DISCHARGE date 
 
Discharged alive from ICU? 
 From ICU to home directly. 
 From ICU to hospital ward. 
 From ICU to another ICU (other hospital) 
( Y / N ) 
Discharged alive from HOSPITAL? 
 Home 
 Nursing home or equivalent 
( Y / N ) 
28-day mortality. Death occurring within 28 days of hospital 
discharge? 
( Y / N ) 
Admitting diagnosis group: 
 Cardiac arrest/ other causes of cardiogenic shock 
 Cardiothoracic surgery 
 Septic shock 
 Medical  
 Neutropenic sepsis/ other haematology & oncology sepsis 
 Surgical 
 Post-operative management: any other speciality 
 

Short Title, Sponsor Ref, Protocol Version and Date 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 38 of 39 
 Haemorrhagic shock 
 Major trauma 
 Gastrointestinal/other medical 
 Post-surgical 
 Acute respiratory failure 
 COPD /asthma exacerbation 
 Pneumonia 
 Other causes 
 Acute renal failure requiring hemofiltration 
 Trauma/neuro-surgical 
 Decompensated liver disease/ acute liver failure 
 Diabetic ketoacidosis/hyperosmotic syndrome 
 Others 
 
PATIENT RESEARCH ENCRYPTED CODE: 
 
 
Chronic diseases 
 Ischaemic heart disease. 
 Congestive heart failure 
 Atrial fibrillation/Atrial flutter 
 Devices 
 Pacemaker (PM) +/- Implantable cardioverter-defibrillator 
(ICD) 
 Cardiac resynchronization therapy (CRT) +/- (ICD) 
 Arterial hypertension 
 Pulmonary hypertension 
 Pulmonary embolus/deep vein thrombosis 
 COPD/Asthma 
 Fibrosis 
 Diabetes mellitus 
 End stage kidney disease (on regular dialysis) 
 Chronic kidney disease or pre-dialysis (NOT on dialysis) 
 Liver disease 
 Morbid obesity. 
 Recent quimiotherapy / radiotherapy (last 30 days) 
 Haematology malignancies 
 Acute myeloid leukaemia (AML) 
 Chronic lymphocytic leukaemia (CLL) 
 Myeloma 
 Lymphoma  
 Other hemato-onco malignancies 
 
Severity scores  
 APACHE II 
 
 

Short Title, Sponsor Ref, Protocol Version and Date 
 
IRAS Ref Number: 227870, The impact of the pH on cardiac output in the critically ill patient 
 
Page 39 of 39 
21 PUBLICATION AND DISSEMINATION POLICY 
 
PUBLICATION IN PEER REVIEW JOURNALS 
 
22 REFERENCES 
 
Adrogué HJ, Madias NE. Management of life-threatening acid-base disorders. First of 
two parts. N Eng J Med 1998; 338:26-34. 
 
Cingolani HE, Faulkner SL, Mattiazzi AR et al. Depression of human myocardial 
contractility with "respiratory" and "metabolic" acidosis. Surgery 1975; 77:427-432. 
 
Shapiro JL. Pathogenesis of cardiac dysfunction during metabolic acidosis: 
therapeutic implications. Kidney Int 1997; Supl 61:S47-S51. 
 
23 APPENDICES 
No appendices 
Appendix 1: PROTOCOL VERSIONS 
Version Stage  
Versions No 3rd 
Version 
Date 
26/03/18 
Appendix No detail the reason(s) for the protocol 
update