Effects of Goal-directed Fluid Management Guided by a Non-invasive Device on the Incidence of Postoperative Complications in Neurosurgery: a Multicenter, Prospective, Randomized, Controlled Study
Phase: NA
Conditions: Surgery Complications
Sponsor: Brno University Hospital

    
 
 
 
 
 
Effects of goal-directed fluid management guided by a non-invasive 
device on the incidence of postoperative complications in neurosurgery: 
a multicenter, prospective, randomized, controlled study 
 
CLINICAL TRIAL PROTOCOL 
 
 
Short title: 
Effects of GDHT using a non-invasive hemodynamic 
monitoring in elective neurosurgery 
Protocol code: 
 
 
NCHGDT 
 
EU CTR: 
 
 
 
2024-511153-21-00  
 
 
 
ClinicalTrials.gov Identifier:  
 
Version | Date:  
 
 
1.2 | 29.05.2024 
 
Sponsor: 
 
 
 
Fakultní nemocnice Brno 
Jihlavská 20 
625 00 Brno, Czech Republic 
 
 
 
 
 
 
 
 
 
 
This trial protocol contains strictly confidential information and is intended solely for the 
guidance of the clinical investigation. This protocol may not be disclosed to parties not 
associated with the clinical research or used for any purpose without the prior written consent 
of the investigator. 
 
 

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STATEMENT 
The following persons undertake to conduct the study “Effects of goal-directed fluid 
management guided by a non-invasive device on the incidence of postoperative complications 
in neurosurgery: a multicenter, prospective, randomized, controlled study” according to this 
protocol and in compliance with applicable national and international requirements, mainly: 
 
• 
Regulation EU No. 536/2014 
• 
Act No. 378/2007 Coll., on Pharmaceuticals, as amended; 
• 
Decree No. 463/2021 Coll., on Detailed conditions governing the conduct of clinical 
trials on medicinal products, as amended; 
• 
Good Clinical Practice – ICH E6(R2); 
• 
Declaration of Helsinki, as amended. 
 
 
 
 
 
 
Signature 
Date 
Person responsible 
for the clinical trial 
on sponsor's side  
prof. MUDr. Roman Gál, 
PhD., 
KARIM FN Brno  
Jihlavská 20, 625 00 Brno 
e-mail: 
gal.roman@fnbrno.cz, 
tel: +420 532 233 847 
 
 
Investigator 
responsible for the 
clinical trial and 
address of the centre 
 
 
 
 
 
 

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CONTENTS 
STATEMENT ................................................................................................................................. 2 
CONTENTS ................................................................................................................................... 3 
LIST OF ABBREVIATIONS .............................................................................................................. 5 
1. 
CLINICAL TRIAL BACKGROUND ................................................................................................................. 7 
 
Goal-directed hemodynamic therapy (GDHT) ....................................................................................... 7 
 
GDHT in neurosurgical interventions..................................................................................................... 7 
1.2.1. 
Spine surgery ................................................................................................................................ 8 
1.2.2. 
Brain surgery ................................................................................................................................. 8 
 
The Starling™ SV System........................................................................................................................ 9 
 
Study rationale ...................................................................................................................................... 9 
 
Anticipated risks and benefits ............................................................................................................... 9 
2. 
TRIAL OBJECTIVES AND ENDPOINTS ....................................................................................................... 11 
 
Aim of the study .................................................................................................................................. 11 
 
Primary objective(s) and endpoint(s) .................................................................................................. 11 
 
Secondary objective(s) and endpoint(s) .............................................................................................. 12 
3. 
TRIAL DESIGN ......................................................................................................................................... 13 
4. 
TRIAL POPULATION ................................................................................................................................ 14 
 
Inclusion criteria .................................................................................................................................. 14 
 
Exclusion criteria .................................................................................................................................. 14 
 
Randomization ..................................................................................................................................... 14 
 
Blinding ................................................................................................................................................ 14 
 
Enrolment stopping rules .................................................................................................................... 14 
 
Premature termination of participation in the trial ............................................................................ 15 
5. 
STUDY TREATMENT ............................................................................................................................... 16 
 
ISOLYTE INF SOL ................................................................................................................................... 16 
5.1.1. 
Pharmaceutical form and route of administration ..................................................................... 16 
5.1.2. 
Marketing-authorization holder ................................................................................................. 16 
5.1.3. 
Storage ........................................................................................................................................ 16 
5.1.4. 
Dosing schedule .......................................................................................................................... 16 
5.1.5. 
Contraindication ......................................................................................................................... 16 
5.1.6. 
Adverse effects ........................................................................................................................... 16 
 
GELASPAN 4% INF SOL ......................................................................................................................... 17 
5.2.1. 
Pharmaceutical form and route of administration ..................................................................... 17 
5.2.2. 
Marketing-authorization holder ................................................................................................. 17 
5.2.3. 
Storage ........................................................................................................................................ 17 
5.2.4. 
Dosing schedule .......................................................................................................................... 18 
5.2.5. 
Contraindication ......................................................................................................................... 18 
5.2.6. 
Adverse effects ........................................................................................................................... 18 
 
Prohibited medication ......................................................................................................................... 18 
 
Concomitant medication ..................................................................................................................... 18 
6. 
COURSE OF THE TRIAL ............................................................................................................................ 19 

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Screening of eligible patients .............................................................................................................. 19 
 
Clinical examinations and assessments ............................................................................................... 19 
 
Study procedures ................................................................................................................................. 21 
 
Biological samples ............................................................................................................................... 23 
7. 
SAFETY ASSESSMENTS ........................................................................................................................... 23 
 
Definitions (according to the Regulation EU No. 536/2014) ............................................................... 23 
 
AE surveillance, recording and documentation ................................................................................... 23 
 
Treatment of AE................................................................................................................................... 24 
 
Assessment of seriousness .................................................................................................................. 24 
 
Assessment of intensity (severity) ....................................................................................................... 24 
 
Assessments of causality ..................................................................................................................... 25 
 
Reporting of SAE and SUSAR ............................................................................................................... 25 
 
Pregnancy ............................................................................................................................................ 26 
8. 
STATISTICS ............................................................................................................................................. 28 
 
Sample size determination .................................................................................................................. 28 
 
Analysis of primary endpoint ............................................................................................................... 28 
 
Analysis of secondary objective(s) and endpoint(s) ............................................................................ 28 
 
Demographic characteristics ............................................................................................................... 29 
 
Missing data ......................................................................................................................................... 29 
9. 
DATA MANAGEMENT AND QUALITY ASSURANCE .................................................................................. 30 
 
eCRF database ..................................................................................................................................... 30 
 
Trial documents, medical records ....................................................................................................... 30 
 
Monitoring and auditing ...................................................................................................................... 30 
 
Steering committee ............................................................................................................................. 31 
 
Medical monitoring ............................................................................................................................. 31 
10. 
ETHICAL ASPECTS ............................................................................................................................... 31 
 
Informed consent procedure ............................................................................................................... 31 
 
Supervision of the informed consent procedure ................................................................................. 31 
11. 
PUBLICATION POLICY ......................................................................................................................... 32 
12. 
FINANCING AND INSURANCE ............................................................................................................. 32 
13. 
REFERENCES....................................................................................................................................... 33 
14. 
SUPPLEMENTS/APPENDICES .............................................................................................................. 35 
 
APPENDIX A AESI definitions ............................................................................................................... 35 
 

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LIST OF ABBREVIATIONS 
 
ADR 
 
Adverse Drug Reaction  
 
AE 
 
Adverse Event 
AESI 
 
Adverse Event of Special Interest 
APCO  
Arterial Pressure Continuous Output 
aPTT 
 
activated Partial Thromboplastin Time 
ARDS  
Acute Respiratory Distress Syndrome 
ASA 
 
American Society of Anesthesiologists 
CIa 
 
Cardiac Index 
CI 
 
Confidence Interval 
CO 
 
Cardiac Output 
CP 
 
Cardiac Power 
CPAP  
Continuous Positive Airway Pressure 
CPI 
 
Cardiac Power Index 
CT 
 
Computerized Tomography 
CTIS 
 
Clinical Trial Information System 
CVP 
 
Central Venous Pressure  
DBP 
 
Diastolic Blood Pressure 
DCI 
 
Delayed Cerebral Ischemia 
DO2I 
 
Delivery Oxygen Index 
DVT 
 
Deep Vein Thrombosis 
ECG 
 
Electrocardiography 
eCRF  
electronic Case Report Form 
eGRF  
estimated Glomerular Filtration Rate 
EVCTM 
EudraVigilance Clinical Trial Module 
e.g. 
 
exempli gratia 
GCP 
 
Good Clinical Practise 
GDHT  
Goal Directed Hemodynamic Therapy 
GOS 
 
Glasgow Outcome Scale 
HR 
 
Heart Rate 
ICF 
 
Informed Consent Form 
ICH E6  
harmonized guideline for good clinical practise 
ICU 
 
Intensive Care Unit 
ICU LOS 
Intensive Care Unit Length of Stay 
i.e. 
 
id est 
IMP 
 
Investigational Medicinal Product 
i.v. 
 
intravenous 
KDIGO  
Kidney Disease Improving Global Outcomes 
LOS 
 
hospital length of stay 
MAP 
 
Mean Arterial Pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
 
Magnetic Resonance Imaging 
NMBA  
neuromuscular blocking agent 
OR 
 
odds ratio 
PE 
 
Pulmonary Embolism 
PEEP  
Positive End-Expiratory Pressure 
RBC 
 
red blood cells 
SADR  
Serious Adverse Drug Reaction 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 

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SBP 
 
Systolic Blood Pressure 
SmPC  
Summary of Product Characteristics 
SpO2  
Saturation of Peripheral Oxygen 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SV 
 
Stroke Volume 
SVI 
 
Stroke Volume Index 
SVV 
 
Stroke Volume Variation 
TCI 
 
Target Controlled Infusion 
TFC 
 
Thoracic Fluid Content 
TIVA 
 
Total Intravenous Anaesthesia 
TPR 
 
Total Peripheral Resistance 
TPRI 
 
Total Peripheral Resistance Index 
UADR  
Unexpected Adverse Drug Reaction 
VET 
 
Ventricular Ejection Time 
 
 

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1. CLINICAL TRIAL BACKGROUND  
 Goal-directed hemodynamic therapy (GDHT) 
Goal-directed hemodynamic therapy (GDHT) is a complex group of interventions aimed at 
improving oxygen delivery and tissue perfusion, successfully used in several surgical 
indications during perioperative period. Many devices - from invasive to minimally invasive - 
can be used to determinate various hemodynamic values, which can be targeted to predefined 
goals through titration of intravenous fluid and vasoactive drugs [1]. GDHT has been shown to 
reduce postoperative complications (e.g. acute kidney disease, pulmonary oedema, wound 
infection) and decrease hospital length of stay in patients undergoing major abdominal, 
urological, gynecological and orthopedic procedures [2,3]. 
Due to the wide application of this methodology in surgery, several meta-analyses processing 
data from clinical trials have been published in the last decade. Jessen et al. [4] identified 76 
comparative studies in which GDHT protocols including fluid therapy to optimize stroke volume 
(or related parameter) were compared with standard care. Analysis of data from 9081 patients 
undergoing non-cardiac surgery showed a moderate-certainty-of-evidence reduction in 
postoperative pneumonia, surgical site infection and anastomotic leakage in the GDHT arms, 
while effects on mortality and hospital length of stay were not demonstrated.  
A systematic review to assess the effect of GDHT exclusively on post-operative pulmonary 
complications in patients undergoing surgery performed Dushianthan et al. [5]. A significant 
reduction in total pulmonary complications (OR 0.74, 95% CI 0.59 to 0.92) in GDHT group was 
demonstrated in a sample of 9548 participants (66 studies in total). Meta-analysis suggests 
that the use of GDHT using fluids with inotropes and/or vasopressors, but not fluids alone, 
reduces the development of post-operative pulmonary infections and pulmonary oedema in 
patients undergoing abdominal and cardiothoracic surgery. The pitfalls of meta-analyses 
focusing on GDHT in general, such as the clinical heterogeneity of patients, interventions and 
outcomes, are pointed out in the review by Kaufmann et al. [6]. Saugel et al. [7] recommend 
consistently including only trials using similar perioperative hemodynamic treatment strategies 
(hemodynamic target variables, target values, and triggered interventions) in meta-analyses to 
avoid oversimplification that could lead to incorrect conclusions. 
 GDHT in neurosurgical interventions 
Patients undergoing major neurosurgery are at risk for inadequate intravascular volumes. Fluid 
overload can contribute to worsening brain oedema. On the other hand, the administration of 
diuretics to reduce brain oedema, reduction of preoperative fluid intake, and intraoperative 
blood loss leads to a decrease in intravascular volume and thus to a decrease in blood flow 
and oxygen supply to the brain and other tissues, resulting in organ dysfunction. The use of 
goal-directed hemodynamic therapy (GDHT) guided by non-invasive measurement of 
hemodynamic parameters aims to optimize the intravascular volume, thereby improve blood 
flow through tissues and reduction of the incidence of postoperative adverse events. 

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1.2.1. Spine surgery 
In contrast to the surgical fields mentioned above, only limited data are currently available on 
the GDHT efficacy in neurosurgery. For spine surgery in the prone position, conflicting results 
from several monocentric studies are available. Picard et al. [8] confirmed that intraoperative 
use of esophageal Doppler and optimalization of perioperative fluid management is feasible 
and may help to reduce the duration of hypotensive episodes during spinal surgical 
procedures. Conversely, a study by Wongtangman et al. [9], despite similar clinical 
characteristics, did not demonstrate significant benefits of the GDHT protocol with respect to 
intraoperative hypotension, blood transfusion, or postoperative complications in patients 
undergoing complex spine surgery. Results published by Abdelhamid et al. also failed to 
demonstrate a benefit of the GDHT compared to conventional fluid management in 66 adult 
patients undergoing spine surgery. The goal-directed fluid management therapy dependent on 
plethysmographic variability index did not reduce the intraoperative total crystalloid 
administration or requirements for blood transfusion [10]. 
Maintanance of targed levels of mean arterial pressure (MAP) and stroke volume (SV) through 
fluid therapy and vasopressor administration with minimally invasive hemodynamic monitoring 
was used by Andrzejewska et al. in a prospective pediatric case-control study in elective 
scoliosis surgery [11]. The GDHT group (n=24, mean age 14 years) showed a significantly 
shorter duration of hypotension (mean arterial pressure < 60 mmHg), reduced hospital stays, 
smaller decreases in postoperative hemoglobin levels and shorter times from the end of 
surgery to extubation.  
1.2.2. Brain surgery 
A study investigating the effects of a GDHT strategy in patients undergoing high-risk brain 
surgery (GDHT group [n=73] vs. control group [n=72]) where appropriate fluid management is 
necessary due to impending brain oedema was conducted by Luo et al. [12]. According to 
published results, ICU length of stay was shorter (3 days [1–5] vs. 6 days [3–11], p = 0.001) 
and ICU costs were lower in the GDHT group. The total number of complications (46 vs. 99, p 
= 0.043) and the proportion of patients who developed one or more complications (19.2 vs. 
34.7%, p = 0.034) were less in the GDHT group compared to patients who received standard 
care.   
The ability of the GDHT approach compared with standard clinical care to reduce the rate of 
delayed cerebral ischemia (DCI) after subarachnoid hemorrhage was investigated by 
Anetsberger et al. [13] in a prospective randomized controlled trial with 108 adult subjects. The 
primary outcome (DCI) occurred in 13% of patients in the GDHT group (n=54) and in 32% of 
patients in the control group (n=54). Moreover, reduced rate of DCI was associated with a 
better functional outcome (GOS=5) 3 months after discharge. 
Another study [14] was designed to assess the influences of arterial pressure continuous 
output (APCO) derived SVV-guided fluid management on postoperative complications and 
outcome in patients undergoing supratentorial neoplasms surgery. Based on data obtained 
from 66 patients, SVV-guided fluid management was associated with a lower incidence of 
postoperative complications and did not induce additional risk of brain oedema (degree of brain 
oedema 1 day postoperatively did not differ between study groups [3 vs. 3, P=0.96]). 

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Finally, a study conducted in 48 patients scheduled for elective craniotomy was designed to 
test whether intraoperative goal-directed fluid management using SVV-guided 0.9% normal 
saline administration could alleviate metabolic acidosis compared with CVP-based fluid 
administration. Contrary to the hypothesis, intraoperative targeted fluid therapy based on SVV 
values from the FloTrac/VigileoTM system did not reduce the severity of metabolic acidosis in 
patients undergoing brain tumor resection compared with CVP-guided fluid therapy [15]. 
 The Starling™ SV System 
The Starling™ SV System is a portable, non-invasive cardiac output (CO) monitoring device 
based on BIOREACTANCE® technology that is capable of predicting response to intravenous 
fluids in critical care situations similar to invasive methods (e.g. esophageal Doppler). It also 
measures heart rate (HR), stroke volume (SV), stroke volume variation (SVV), ventricular 
ejection time (VET), mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic 
blood pressure (DBP), saturation of peripheral oxygen (SpO2) and thoracic fluid content (TFC). 
In addition, the system calculates some other clinical parameters such as cardiac index (CIa), 
stroke volume index (SVI), total peripheral resistance (TPR), total peripheral resistance index 
(TPRI), cardiac power (CP), cardiac power index (CPI) or oxygen delivery index (DO2I). The 
Starling™ SV System is registered in the Registry of Medicinal Devices under reference 
number 00538564 and is not subject to the obligation of any clinical tests of the medical device 
in this clinical trial. Only limited data have been published on its use in neurosurgery [16], the 
expansion of this knowledge is one of the goals of this clinical trial. 
 Study rationale 
Surgical procedures, particularly in neurosurgery, pose significant challenges in fluid 
management. The balance between maintaining adequate intravascular volume to ensure 
sufficient organ perfusion while avoiding fluid overload is crucial for optimizing patient 
outcomes. Neurosurgical patients face unique factors contributing to fluid imbalance, including 
preoperative diuretic use, decreased oral intake, and the risk of intraoperative blood loss. 
These factors can lead to hypovolemia, compromising organ perfusion and increasing the risk 
of complications. Conversely, excessive fluid administration can exacerbate issues like 
cerebral edema and compromise cardiac function. 
The goal-directed hemodynamic therapy (GDHT) approach has shown promise in various 
surgical subspecialties, demonstrating reductions in perioperative complications, shorter 
hospital stays, and decreased costs. However, its application in neurosurgery remains 
understudied. The primary aim of this study is to determine whether optimizing fluid 
management during elective neurosurgical procedures reduces the occurrence of 
postoperative adverse events in adult patients compared to standard care.  
 Anticipated risks and benefits 
The feasibility and safety of a GDHT approach using the non-invasive Starling™ SV System 
in neurosurgery was evaluated in a pilot study (34 adult subjects). No patient had 
unsatisfactory relaxation of brain tissue after surgery or brain oedema requiring therapy during 
surgery or 24 hours after surgery. Major complications occurred in two (11.8 %) patients in the 

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GDHT group and six (35.3%) patients in the control group (p = 0.105) [17]. The Starling™ SV 
System is an approved medical device, which will be used in accordance with its stated 
purpose and manufacturer’s recommendations. As part of this clinical trial, only registered 
medicinal products that are standardly used in the given indication will be used, so there is no 
assumption of the emergence of new safety signals resulting from the use of these products.  
The clinical outcome of an individual participant in this trial may or may not be improved. If 
effective, GDHT might help to optimize intravascular volume, prevent fluid overload or 
hypovolemia and thereby reduce the incidence of postoperative adverse events in adult 
patients undergoing elective neurosurgery. As elective neurosurgical procedures are generally 
high-risk, all participants in this clinical trial will be provided with proper peri- and post-operative 
care and immediate medical attention will be provided in case of any unexpected events. 
 
 

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2. TRIAL OBJECTIVES AND ENDPOINTS 
 Aim of the study 
This study aims to assess the safety and efficacy of GDHT using the non-invasive Starling™ 
SV System in elective neurosurgery. The tested group of patients (n=70) will be compared with 
a control group (n=70), where hemodynamic management will be guided by standard vital 
signs monitoring. 
 Primary objective(s) and endpoint(s) 
The primary objective of the clinical trial is to determine the effect of GDHT guided by the 
non-invasive Starling™ SV System on the incidence of postoperative complications in patients 
undergoing neurosurgical intervention.  
 
The following primary endpoints will be monitored to evaluate the primary objective:   
1.) Incidence of adverse events and reactions according to following Adverse Events of Special 
Interest (AESI) in both study groups. 
 
Monitored parameters (AESI): (YES/NO) 
Detailed definitions and grading of individual AESI can be found in Appendix A 14.1 
▪ 
Acute Kidney Injury (stage 2, 3 according to KDIGO guidelines) 
▪ 
Acute Respiratory Distress Syndrome (ARDS, according to Berlin definition of 
Respiratory Distress Syndrome) 
▪ 
Arrhytmia (moderate/severe) 
▪ 
Cardiac arrest 
▪ 
Cardiogenic pulmonary oedema (moderate/severe) 
▪ 
Deep vein thrombosis (DVT; moderate/severe) 
▪ 
Pulmonary embolism (PE) 
▪ 
Gastrointestinal bleed (moderate/severe) 
▪ 
Infection, source uncertain (moderate/severe) 
▪ 
Laboratory confirmed bloodstream infection (moderate/severe) 
▪ 
Myocardial infarction (moderate/severe) 
▪ 
Pneumonia (moderate/severe) 
▪ 
Paralytic ileus (moderate/severe) 
▪ 
Postoperative haemorrhage (moderate/severe) 
▪ 
Stroke (moderate/severe) 
▪ 
Brain oedema (CT or MRI proven; moderate/severe) 
▪ 
Surgical site infection (superficial; moderate/severe) 
▪ 
Surgical site infection (deep; moderate/severe) 
▪ 
Surgical site infection (organ/space; moderate/severe) 
▪ 
Urinary tract infection (moderate/severe) 

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 Secondary objective(s) and endpoint(s) 
The secondary objective is to investigate the efficacy and additional safety parameters of 
GDHT guided by non-invasive advanced hemodynamic monitoring versus hemodynamic 
management guided by standard vital signs monitoring. 
 
Secondary endpoints are as follows: 
1.) Additional safety information 
Monitored parameters: 
▪ 
Duration of surgery (min) 
▪ 
LOS (day of admission – day of discharge will be counted as 1 day) 
▪ 
ICU LOS (day of admission – day of discharge will be counted as 1 day) 
▪ 
28-day mortality (number of patients who are not alive 28 days after randomization) 
▪ 
Descriptive analysis of the incidence of any adverse events and reactions 
 
2.) Comparison of hemodynamic characteristics and their changes over time between study 
groups 
Monitored parameters: 
▪ 
MAP (mmHg; before, after surgery) 
▪ 
HR (Bpm; before, after surgery) 
▪ 
SVV (%; before, after surgery) 
▪ 
Number of episodes of hypotension1  
▪ 
Number of vasopressor administrations   
3.) Comparison of laboratory values of selected blood parameters and their changes over time 
between study groups 
Monitored parameters: 
▪ 
Hemoglobin (g/l; before, after surgery and 24 hours after surgery) 
▪ 
Plasma lactate level (mmol/L; before, after surgery and 24 hours after surgery) 
4.) Comparison of fluid balance and fluid therapy between study groups 
Monitored parameters: 
▪ 
Volume of blood loss (ml/kg; during surgery2 and in the 24-hour postoperative period) 
▪ 
Urinary output (ml/kg/hod; during surgery2 and in the 24-hour postoperative period) 
▪ 
Number of administered units of packed RBC (during surgery2 and in the 24-hour 
postoperative period) 
                                               
 
 
1 MAP bellow 65 torrs [18] 
 
2 duration of surgery is considered as the time from the skin incision to the suture of the dura 

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▪ 
Number of subjects receiving transfusion (during surgery2 and in the 24-hour 
postoperative period) 
▪ 
Crystalloid and colloid solutions consumption (type and total volume of infusion during 
surgery2 and in the 24-hour postoperative period) 
▪ 
Boluses of crystalloids (ml; during surgery2) 
 
3. TRIAL DESIGN 
The NCHGDT is a multicenter, prospective, randomized, controlled trial comparing the efficacy 
and safety of two approaches to fluid management in elective neurosurgery; GDHT guided by 
the non-invasive Starling™ SV System versus hemodynamic management guided by standard 
vital signs monitoring. The study will be conducted at the University Hospital Brno, Czech 
Republic and in other Czech centers that have appropriate equipment for advanced 
hemodynamic monitoring. Optimal standard treatment will be achieved in both arms of the 
study using the current best treatment protocol. The anticipated sample size is 140 patients 
randomized into study groups in a 1:1 allocation ratio and followed up for 28 days after surgery. 
End of study is defined as the time of completion of the 28-day follow-up in the last patient. 
The expected duration of this clinical trial is 3 years. 
 
 

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4. TRIAL POPULATION 
 Inclusion criteria 
Subjects will be eligible for the trial if they meet all of the following criteria: 
1. Age ≥ 18 years  
2. Elective brain surgery with an expected duration ≥ 2 h 
3. Category 1-3 according to the ASA Physical Status Classification 
4. Lateral or supine operative position 
5. Signed the relevant informed consent form (more in Chapter 10.1) 
 Exclusion criteria 
Subjects will not be eligible for the trial if they meet any of the following criteria: 
1. Category 4 according to the ASA Physical Status Classification 
2. Surgery for traumatic brain injury or acute hemorrhagic stroke  
3. Awake brain surgery 
4. Osmotherapy before surgery (with the exception of prophylactic administration of 
osmotic agents according to institutional standards) 
5. Unavailability of hemodynamic monitoring data 
6. Cardiac arrhythmia with irregular cardiac rhythm 
7. Known hypersensitivity to the active substance or to any of the excipients of IMP (see 
Chapter 5) 
8. Pregnancy and lactation 
 Randomization  
Participants will be randomized in a 1:1 ratio to the two study arms (GDHT or STANDARD) 
using the eCRF REDCap database shortly before surgery by a member of the study team. 
 Blinding  
The neurosurgeon, ICU staff and members of the study team collecting data will be blinded. 
The hemodynamic monitor will be placed in the operating room during all study interventions 
so that the neurosurgeon cannot see whether it is being used or not. Other study staff and 
attending physicians and other staff will not be blinded, as blinding is not possible when 
conducting the study intervention. The data management group and statisticians will work with 
a pseudo-anonymized data set. 
 Enrolment stopping rules 
Enrolment of new subjects into the trial may be stopped in situations that could lead to an 
immediate risk to patients (e.g. epidemics of serious infectious diseases, etc.) or if a new 
toxicity of the study medication is newly identified. 

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 Premature termination of participation in the trial 
Reasons for early termination of a patient's participation include: 
• 
Withdrawal of informed consent (subject's decision to withdraw for any reason); 
• 
Important deviation in the process of informed consent (Chapter 10); 
• 
Life-threatening adverse reaction related with IMP or study intervention at the discretion 
of the investigator; 
• 
Pulmonary oedema or cardiac decompensation is suspected; 
• 
Newly-emerged pregnancy of a participant after the enrolment; 
Subjects can terminate their participation prematurely at any time at their request for any 
reason, but they must notify the investigator. The investigator must contact the sponsor to 
report the premature discontinuation. 
The investigator must: 
• 
Instruct the participant about the right on early termination of participation; 
• 
Assure him/her that the end of participation will not affect the attitude of the physician, 
or further treatment and its quality; 
• 
Ask for discussing this decision with the investigator in advance; 
• 
Make a note in the patient's medical records and eCRF about the date of early 
termination of participation. 
The sponsor reserves the right to discontinue the study at any time if there is a significant 
safety concern, or insufficient recruitment despite intensified efforts to enrol patients, or if 
repeated poor study documentation occurs at a site. The trial can be discontinued by the 
decision of the regulatory authority or ethics committee, as well. 
 
 

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5. STUDY TREATMENT  
 ISOLYTE INF SOL 
ISOLYTE INF SOL was chosen as a model preparation of crystalloid solution for intravenous 
administration in this clinical trial (ATC code: B05BB01). Detailed information on its 
pharmacodynamics, pharmacokinetics, excipients and other characteristics can be found in 
the SmPC. 
Quantitative composition: 
 
500 ml 
1000 ml 
Sodium Acetate Trihydrate 
2.32 g 
4.63 g 
Sodium Chloride 
3.01 g 
6.02 g 
Potassium Chloride 
0.15 g 
0.30 g 
Magnesium Chloride Hexahydrate 0.15 g 
0.30 g 
 
Electrolytes: Na+ 137.0 mmol/l, K+ 4.0 mmol/l, Mg2+ 1.5 mmol/l, Cl- 110.0 mmol/l, CH3COO- 
34.0 mmol/l 
5.1.1. Pharmaceutical form and route of administration 
Solution for infusion; intravenous administration 
5.1.2. Marketing-authorization holder 
Fresenius Kabi s.r.o., Na Strži 1702/65, Nusle, 140 00 Praha 4, Česká republika 
5.1.3. Storage 
Shelf life in intact packaging (before opening): Freeflex - 3 years, KabiPac - 3 years. Protect 
from cold or frost. 
5.1.4. Dosing schedule 
Dosage will be chosen and adjusted according to the investigator's decision in accordance 
with SmPC. A detailed description of the recommended dosage is included in the Chapter 6.3.  
5.1.5. Contraindication 
Administration of IMP is contraindicated in cases of:  
▪ 
fluid overload (hyperhydration; especially with pulmonary oedema and congestive heart 
failure),  
▪ 
severe renal dysfunction, 
▪ 
metabolic alkalosis and  
▪ 
hyperkalemia. 
5.1.6. Adverse effects 
The following adverse effects have been reported during administration of electrolyte solutions: 

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1. Disorders of metabolism and nutrition 
▪ 
hyperhydration and heart failure in patients with heart failure or pulmonary oedema 
(very common ˃1/10) 
▪ 
oedema due to excess water/sodium in the body (frequency not known) 
2. General disorders and reaction at the site of application 
▪ 
febrile response, injection site infection, local pain or reaction, vein irritation, venous 
thrombosis or phlebitis extending from the injection site, and extravasation 
 
At high doses, the dilution effect can often lead to dilution of individual blood components, e.g. 
coagulation factors and other plasma proteins, and to a decrease in hematocrit. In case of 
adverse effects, the infusion must be interrupted. 
 
 GELASPAN 4% INF SOL  
GELASPAN 4% INF SOL was chosen as a model preparation of colloid solution for intravenous 
administration in this clinical trial (ATC code: B05AA06). Detailed information on its 
pharmacodynamics, pharmacokinetics, adverse effects, excipients and other characteristics 
can be found in the SmPC. 
Quantitative composition: 
 
1000 ml 
Gelatin Succinate 
40.0 g 
Sodium Chloride 
5.55 g 
Sodium Acetate Trihydrate 
3.27 g 
Potassium Chloride 
0.30 g 
Calcium Chloride Dihydrate 
0.15 g 
Magnesium Chloride Hexahydrate 0.20 g 
 
Electrolytes: Na+ 151.0 mmol/l, K+ 4.0 mmol/l, Mg2+ 1.0 mmol/l, Ca2+ 1.0 mmol/l, Cl- 103.0 
mmol/l, CH3COO- 24.0 mmol/l 
5.2.1. Pharmaceutical form and route of administration 
Solution for infusion; intravenous administration 
5.2.2. Marketing-authorization holder 
B. Braun Melsungen AG, Carl-Braun-Str. 1, 34212 Melsungen, Germany  
5.2.3. Storage 
Shelf life in intact packaging (before opening): polyethylene bottles - 2 years, plastic bags 
(PVC-free) - 2 years. Store at a temperature of up to 25 °C. Protect from frost. 
 
 

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5.2.4. Dosing schedule 
Dosage will be chosen and adjusted according to the investigator's decision in accordance 
with SmPC. A detailed description of the recommended dosage is included in the Chapter 6.3. 
5.2.5.  Contraindication 
▪ 
hypersensitivity to solutions containing gelatin or to any of the excipients  
▪ 
hypersensitivity to galactose-α-1,3-galactose (alpha-gal) or known allergy to red meat 
(mammal meat) and offal  
▪ 
hypervolemia  
▪ 
hyperhydration  
▪ 
acute congestive heart failure 
5.2.6. Adverse effects 
The following adverse effects have been reported during administration of Gelaspan 4%: 
▪ 
Very common (≥ 1/10): decreased hematocrit and decreased concentration of plasma 
proteins 
▪ 
Common (≥ 1/100 to <1/10): relatively large doses of Gelaspan 4% cause dilution of 
coagulation factors and can therefore affect blood coagulation. After administration of 
large doses of Gelaspan 4%, the value of prothrombin time may increase and the 
activated partial thromboplastin time (aPTT) may be prolonged. 
▪ 
Rare (≥ 1/10,000 to <1/1,000): anaphylactic/anaphylactoid reactions up to shock 
▪ 
Very rare (< 1/10,000): tachycardia, hypotension, fever, chills 
▪ 
Not known: nausea, vomiting, abdominal pain, decreased oxygen saturation 
 
In the event of an anaphylactoid reaction, the infusion must be stopped immediately and the 
usual acute treatment instituted. 
 Prohibited medication 
No prohibited medication is defined for the purposes of this clinical trial. 
 Concomitant medication 
Fluids, vasopressors and inotropes listed in Chapter 6.3 (see detailed information on dosage) 
can be used to treat hypovolemia, hypotension and low cardiac output respectively.     
 
 

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6. COURSE OF THE TRIAL 
 Screening of eligible patients 
Adult patients scheduled for elective neurosurgery will be screened for eligibility criteria after 
admission to the hospital. Study team members will perform the screening, and the principal 
investigator will regularly audit the accuracy of screening. Patients will be included if they meet 
all inclusion criteria and none of the exclusion criteria. After obtaining informed consent, each 
patient will be randomised to one of the trial arms. For details on obtaining the informed 
consent see Chapter 10.1 
 
 Clinical examinations and assessments 
During the trial course, subjects will be monitored during hospitalization and after discharge. A 
summary of scheduled procedures is outlined in Chapter 6.3. For a graphic summary see 
Table 1. 

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Table 1: Clinical trial schedule 
 
STUDY PERIOD 
 
Screening 
Allocation 
Post-allocation 
Hospital 
discharge 
Follow-up 
Premature termination 
TIMEPOINT 
D-3-0 
 
D1 
D2 
D3-28 
D28 
Anytime 
ENROLMENT: 
Eligibility criteria 
X 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
Pregnancy testing1 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
ASSESSMENTS: 
Demographic data2 
 
X 
 
 
 
 
 
Fluid therapy3 
 
 
X 
X 
 
 
 
Laboratory testing4 
 
 
X 
X 
 
 
 
Hemodynamics5 
 
 
X 
 X* 
 
 
 
Adverse events 
 
 
X 
X 
X 
X 
X 
Postoperative complications (AESI6) 
 
 
X 
X 
X 
X 
X 
Blood loss7 
 
 
X 
X 
 
 
 
Urinary output8 
 
 
X 
X 
 
 
 
Transfusion products consumption9 
 
 
X 
X 
 
 
 
Duration of surgery (min) 
 
 
X 
 
 
 
 
ICU LOS (days) 
 
 
 
 
X 
 
 
LOS (days) 
 
 
 
 
X 
 
 
28-day mortality 
 
 
 
 
 
X 
 
Reason for premature termination 
 
 
 
 
 
 
X 
1 urine pregnancy testing  
2 age, sex, weight 
3 type and volume (ml) during surgery and in the 24-hour postoperative period (for more details see Chapter 2.3, point 4.) 
4 hemoglobin, plasma lactate level (for more details see Chapter 2.3, point 3.) 
5 MAP, HR, SVV, number of hypotension episodes, number of vasopressor administrations (for more details see Chapter 2.3, point 2.) 
6 for more details see Chapter 2.2 
7 volume (ml/kg) during surgery and in the 24-hour postoperative period 
8 volume (ml/kg/hod) during surgery and in the 24-hour postoperative period 
9 number of administered units of packed RBC during surgery and in the 24-hour postoperative period 
*except SVV 
 
 
 
 
 

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 Study procedures 
Day -3 to 0 
• 
Eligibility screen – inclusion and exclusion criteria 
• 
Informed consent procedure (Chapter 10.1) 
• 
Pregnancy testing (see Chapter 7.8) 
• 
Demographic data  
• 
Randomization (more in Chapter 4.3) 
 
Day 1 
• 
Assessment of hemoglobin and plasma lactate level 
• 
Recording blood loss and urinary output during and after surgery 
• 
Transfusion products consumption 
• 
Crystalloid and colloid solution consumption 
• 
Monitoring of hemodynamic parameters 
• 
Monitoring of adverse events and reactions including postoperative complications of 
special interest  
Prior to surgery, study participants will receive regular premedication according to hospital 
standards. 
General anaesthesia will be induced by intravenous administration of propofol. For attenuation 
of the hemodynamic response to laryngoscopy, opioid will be added. To facilitate intubation, a 
neuromuscular blocking agent (NMBA) will be used. After tracheal intubation, mechanical 
ventilation will be commenced with the following settings: tidal volume of 8–10 ml/kg and 
respiratory rate to maintain an end-tidal CO2 of 30–35 mmHg. Anaesthesia will be maintained 
with propofol infusion using TCI (target controlled infusion) or TIVA (total intravenous 
anaesthesia) and additional doses of opioids and relaxants will be administered at the 
discretion of the attending anaesthesiologist. The patients’ temperature will be maintained at 
36–37 °C. 
Both groups will receive standard monitoring of vital signs through continuous 
electrocardiography, pulse oximetry, end-tidal CO2 measurement, and invasive monitoring of 
arterial blood pressure.  
In the STANDARD arm, perioperative hemodynamic management and postoperative care will 
be at the discretion of the attending anaesthesiologist and intensivist, respectively. 
Hypotension with MAP < 65 mmHg will be managed with administration of a 250-ml bolus of 
balanced crystalloid over 10 min or 250-ml bolus of colloid over 5 min. The choice of fluid and 
number of boluses will be at the discretion of attending anaesthesiologist. If fluids are 
considered ineffective, a vasopressor will be added.  
In the GDHT arm, non-invasive hemodynamic monitoring will be used (Starling™ SV 
hemodynamic monitor, Cheetah Medical Inc., 600SE Maritime Ave Suite 220, Vancouver, WA, 
USA) in addition to the monitoring used in the STANDARD arm. The Starling SV monitor uses 

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patented Bioreactance® technology and requires placement of only four sensors, which are 
skin electrodes similar to those used for ECG monitoring.  
The extended monitoring will begin after the induction of general anaesthesia and resolution 
of any hypotension caused by the induction of general anaesthesia. This hypotension will be 
resolved with fluid bolus and vasopressor administration if necessary. Subsequently, a basal 
infusion will be initiated with balanced crystalloid solution at 3 ml.kg−1.h−1 with an infusion pump. 
We will then determine the optimal CIa, defined by a value of at least 2,5 l.min.m−2, a stroke 
volume variation (SVV) below 15%, and a MAP above 65 mmHg. If the CIa will not be optimal, 
appropriate interventions will be performed to achieve optimal values.  
In case of SVV>15%, a 250-ml bolus of crystalloid over 10 min will be administered. This 
process will be repeated until the SVV decrease below 15%. If the SVV is above 15%, and the 
CIa decrease with administration of a bolus of crystalloid, inotropic therapy will be introduced 
(dobutamine) at a dose of 2,5 mcg/kg/min and increased if necessary to achieve CIa>2,5 
l.min.m−2 
If hypotension occurs with MAP below 65 mmHg and SVV below 15%, norepinephrine therapy 
will be initiated.  
After determining the optimal CIa, we will aim to maintain the SVV below 15% to preserve the 
optimal CIa. When the SVV exceed 15%, and the CIa is lower than optimal, a crystalloid bolus 
(250 ml) will be administered. If, after administration of crystalloid, the SVV decrease below 
15%, the CIa will be verified. If the CIa is optimal, no further action will be taken. If the CIa remain 
suboptimal, the crystalloid bolus will be repeated.  
If the SVV remain above 15% despite crystalloid bolus administration, the CIa will be verified. 
If the CIa increase, no further action will be taken. If the CIa is suboptimal, inotropic therapy will 
be introduced (dobutamine).  
In case of hypotension with MAP below 65 mmHg concurrent with an SVV above 15%, a 250- 
ml balanced crystalloid bolus will be administered. If hypotension with MAP below 65 mmHg 
and SVV below 15% occurs, norepinephrine therapy will be started. 
Day 2 
• 
Assessment of hemoglobin and plasma lactate level 
• 
Recording blood loss and urinary output during and after surgery 
• 
Transfusion products consumption 
• 
Crystalloid and colloid solution consumption 
• 
Monitoring of hemodynamic parameters except SVV 
• 
Monitoring of adverse events and reactions including postoperative complications of 
special interest  
 
Day 3 to Day 28 / ICU discharge (whichever comes first) 
• 
Checking adverse events and adverse reactions (with special interest in postoperative 
complications of special interest) 
• 
Discharge from ICU and hospital 

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Day 28 
• 
Checking adverse events and adverse reactions (outpatient or telephone call) 
• 
Mortality assessment 
 Biological samples 
Blood samples will be taken following local practice and analysed in the respective clinical 
laboratory facility of the trial centre. No other biological specimens will be obtained or stored in 
this trial. 
 
7. SAFETY ASSESSMENTS 
Before the start of the clinical trial, all investigators will undergo training in pharmacovigilance 
requirements and procedures.  
 Definitions (according to the Regulation EU No. 536/2014) 
For clinical trials, effective legislation has introduced the following definitions. 
Table 2: Definitions of safety events 
Adverse event 
AE 
Any untoward medical occurrence in a patient or clinical 
trial subject administered a medicinal product and which 
does not necessarily have a causal relationship with this 
treatment. 
Adverse drug reaction 
ADR 
All untoward and unintended responses to an 
investigational medicinal product related to any dose 
administered 
Serious adverse event 
SAE 
A serious adverse event/reaction is any untoward medical 
occurrence or effect that at any dose: 
• 
Results in death; 
• 
Is life-threatening; 
• 
Requires hospitalization or extension of 
existing hospitalization; 
• 
Results in persistent or significant disability or 
incapacity; 
• 
Is a congenital anomaly or birth defect. 
Serious adverse 
reaction 
SADR 
Unexpected adverse 
reaction 
UADR 
Adverse reaction, the nature, severity, or outcome of which 
is not consistent with the product information (SmPC) 
Suspected unexpected 
serious adverse 
reaction 
SUSAR 
Any suspected adverse reaction related to the study 
treatment that is both serious and unexpected. 
 AE surveillance, recording and documentation 
AE could be diseases or symptoms which occur or worsen after the enrolment of a patient in 
the clinical trial. All AEs need to be documented, no matter if the investigator suspects a causal 

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connection to the study medication. AE will be monitored and documented from the day of 
giving informed consent until the end of participation in the study (i.e., End of Study Visit 
or Premature withdrawal Visit).  
Subjects will be instructed to report any AEs that they experience to the investigator. 
The investigator should actively ask about AEs and record the potential AE. 
Each AE should be described, documented in the eCRF, and evaluated to determine: 
• 
Seriousness (see Chapter 7.4); 
• 
Severity (see Chapter 7.5); 
• 
Causality, i.e. relation to the study medication (see Chapter 7.6); 
• 
Duration (start and end dates or whether it continues). 
• 
Action taken (no action taken; study medication discontinued; prolongation of the 
ongoing hospitalization; administration of a drug etc.) 
AE needs to be followed until its resolution, i.e. until it subsides, stabilizes, becomes chronic, 
or the subject dies. 
If AE fulfils the criteria of SAE, separate form in eCRF must be completed (see Chapter 7.7).  
AEs will be recorded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
The most recent MedDRA version at the start of the study will be used. 
 Treatment of AE 
A patient with an AE must receive appropriate therapy. The patient will remain under medical 
supervision until the investigator determines that the AE has been resolved. 
 Assessment of seriousness 
AE is considered serious if it fulfils the definition in Chapter 7.1. 
Some situations can be considered as SAE even if they do not fulfil the criteria of the 
definition. These are important medical events that may not be immediately life-threatening, or 
result in death, or hospitalization but may endanger the subject, or may require intervention to 
prevent one of the other outcomes listed in the definition above. These should also be 
considered SAE – e.g., allergic bronchospasm, convulsions, or other states requiring 
treatment. If AE fulfils the criteria of SAE, a separate Serious Adverse Event Form have to 
be completed and sent to the sponsor. For the procedure see Chapter 7.7. 
 Assessment of intensity (severity) 
The intensity (severity) of an AE should be evaluated according to these 5 categories: 
Grade 1 
AE is asymptomatic or mildly symptomatic, requires only observation, no medical intervention 
Grade 2 
AE with medium intensity, requires local, non-invasive, or small-scale treatment 
Grade 3 
AE is medically significant, requires hospitalization or extension of ongoing hospitalization, but 
it is not directly life-threatening 

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Grade 4 
AE is life-threatening and requires urgent significant medical intervention 
Grade 5 
AE leads to death 
 
 Assessments of causality 
To assess the relation between administration of the study medication and the AE, the 
following definitions apply: 
• 
Related – The event is known to occur with the study medication, there is a reasonable 
possibility that the study medication caused the AE, or there is a temporal relationship 
between the study medication and AE. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study medication and the AE.  
• 
Not related – There is not a reasonable possibility that the administration of the study 
medication caused the AE, there is no temporal relationship between the study 
medication and AE onset, or an alternate aetiology has been established. 
 Reporting of SAE and SUSAR 
 
Sponsor will check the SAE Form completeness and formal plausibility. If required, queries will 
be made.  
If all required information is not available at the time of the initial SAE report, follow-up reports 
should be sent by the investigator. Follow-up report should use a new blank SAE Form and 
the investigator should clearly state that this is a follow-up and give the date of the initial report. 
The investigator must update the SAE form and submit any supporting documentation (e.g., 
lab results, subject discharge summary, autopsy report) within 24 hours of receipt of this new 
information. The follow-up SAE report should describe whether the event has resolved or 
continues, if and how it was treated and whether the patient continued or withdrew from trial 
participation.  
All SAEs should be followed until their resolution, i.e., they subside, stabilize, become chronic, 
or the subject dies followed. In case of early termination because of SAE occurrence, the 
subject should be followed until SAE resolution. All necessary extra visits will be recorded in 
the eCRF as "Unscheduled visits". 
In the case of death, a copy of the autopsy record should be added, if available. If the death of 
the subject complies with the definition of SUSAR (see Chapter 7.1), it will be reported as 
SUSAR (see below). 
The investigator is obliged to report any SAE within 24 hours after he/she learns 
about it to the sponsor using Serious Adverse Event Form (SAE Form). The blank 
forms are stored in the Investigator’s Site File. Reporting should be done by e-mail: 
farmakovigilance@med.muni.cz AND martina.kyselakova@med.muni.cz.  

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Sponsor has full responsibility for the safety of the clinical trial. Further reporting of AEs 
to the competent authorities according to the legal requirements is the responsibility of the 
sponsor. 
Reporting of SUSAR 
SAE related to the study medication fulfilling the criterion of unexpectedness (i.e., SUSAR) 
must be reported by the sponsor to the EudraVigilance database (module EVCTM), at the 
latest 15 days after it becomes known. Sponsor will also inform all Investigators involved in the 
trial. Reporting to the EudraVigilance database will be performed via regulatory authority 
according to the agreement between the sponsor and the regulatory authority. In case of a 
fatal or life-threatening SUSAR, the sponsor will report all relevant information immediately, at 
the latest 7 days after the event becomes known. Any subsequent additional information is 
forwarded within the next 8 days if necessary.  
 Pregnancy 
 
Pregnancy and breastfeeding are exclusion criteria, and thus, pregnant and breastfeeding 
women cannot be included in the study. Pregnancy testing (hCG, urine sample) is obligatory 
at enrolment in women of childbearing potential3. Newly-emerged pregnancy in the 
hospitalization and follow-up phase of the trial is highly unlikely. However, if a subject becomes 
pregnant during the trial course, she must inform the investigator. 
Pregnancy should be followed by the investigator until completion. If it ends for any reason 
before the anticipated date, the investigator should notify the sponsor. At the completion of the 
pregnancy, the investigator will document the outcome of the pregnancy. If the outcome of the 
pregnancy meets the criteria for classification as SAE (e.g., spontaneous abortion, stillbirth, 
                                               
 
 
3 Childbearing potential is limited by the period from menarche to the onset of postmenopause (i.e. the 
period in which menstruation last occurred physiologically at least 12 months ago). The onset of 
postmenopause will not be verified by FSH testing, in case of doubt, the physician will consider the 
woman as a woman with childbearing potential. 
 
 
The Investigator should report the pregnancy to the Sponsor within 24 hours of 
learning of its occurrence using Pregnancy Form. This announcement will be done 
by e-mail: farmakovigilance@med.muni.cz AND martina.kyselakova@med.muni.cz. 
Person responsible for pharmacovigilance 
MUDr. Martina Kyseláková 
Tel: +420 778 517 417  
E-mail: farmakovigilance@med.muni.cz  
E-mail: martina.kyselakova@med.muni.cz   
Deputy to the responsible person 
MUDr. Kateřina Nerušilová 
Tel: +420 737 657 454 
E-mail: farmakovigilance@med.muni.cz  
E-mail: nerusilova@med.muni.cz  

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neonatal death, postpartum complication, or congenital anomaly), the investigator should 
follow the procedures for reporting an SAE (see Chapter 7.7). 
 

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8. STATISTICS 
A separate Statistical Analysis Plan (SAP) will be prepared to provide details on the approach 
to analyses. The SAP will be finalized before the database lock. All eventual deviations from 
the SAP will be described and justified in the relevant part of the Clinical Trial Report. 
As a general approach for the descriptive analysis, the following statistics will be provided for 
continuous variables: number of subjects with available data (n), mean, standard deviation, 
median, 25% and 75% quartile, minimum and maximum. Categorical and binary variables will 
be presented as absolute and relative frequencies together with 95% CI, if appropriate. 
For comparison between study arms two-sample Welch’s t-test or its nonparametric alternative 
(Mann-Whitney test) will be used for continuous variables, Pearson’s Chi-square test or Fisher 
exact test, if the assumptions for Chi-square test are not met, for categorical parameters.  
Welch’s t-test will be used if the normality is not rejected; otherwise Mann-Whitney test will be 
used for comparison of continuous variables. The normality will be checked visually (using 
histograms and Q-Q plots) and explored using Shapiro-Wilk test and eventually evaluated as 
a combination of visual assessment and statistical testing. If the normality of the data is not 
rejected, the difference between study groups will be expressed using difference between the 
means and 95% CI. Otherwise, the difference between the medians will be presented together 
with 95% CI calculated using bootstrap method. 
As there is no formal statistical hypothesis to be tested, all statistical tests will be two-sided 
and performed on exploratory basis only. P-values < 0.05 will constitute statistically significant 
differences. 
 Sample size determination 
A sample size of 140 participants (70 in each arm) was calculated to detect the difference 
between arms at two-sided type I error of 0.05 and power of 80% according to results of the 
pilot study [17]. Number of patients with any AESI was 33% in a control group and 11% in 
interventional group. A 10% dropout rate was already included in a total number. 
 
 Analysis of primary endpoint 
The primary endpoint will be evaluated as number and percentage of patients with any AESI 
defined in section 2.2 and compared between study arms by Chi-square test or Fisher exact 
test. The difference between proportions including its 95% CI will be calculated as well. 
FAS and PPS will be used for the analysis of the primary endpoint. 
 Analysis of secondary objective(s) and endpoint(s) 
All secondary endpoints will be analysed using FAS. Descriptive statistics and statistical tests 
described above will be used based on the type of variables and fulfilment of criteria for the 
usage of particular tests.  

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The incidence of any adverse events and reactions will be analysed descriptively and 
compared between study arms in the same manner as the primary endpoint 
 
Duration of surgery will be analysed descriptively and compared between study arms. 
  
ICU and hospital length of stay (LOS) will be calculated as a number of days between 
admission and discharge, analysed descriptively and compared between study groups. 
 
28-days mortality will be evaluated as a number and percentage of patients who are not alive 
28 days after randomization and compared between study arms. 
 
Hemodynamic characteristics, blood parameters (hemoglobin, plasma lactate level) and their 
changes over time will be analysed descriptively and compared between study arms. 
 
Fluid balance and fluid therapy will be analysed descriptively and compared between study 
arms. 
 Demographic characteristics 
Demographic characteristics of patients will be analysed descriptively overall and by study 
arms.  
 Missing data 
In general missing data are not planned to be imputed. For secondary endpoints defined as 
duration (duration of surgery, ICU and hospital length of stay (LOS)) missing dates and/or 
times will be imputed based on the rules further specified in the SAP, unless missing due to 
premature discontinuation.  
For the rest of continuous variables defined as secondary endpoints proportion of missing data 
will be evaluated, unless missing due to premature discontinuation. If more than 50% of the 
expected data are missing, imputation techniques might be applied within the scope of 
sensitivity analysis. Further details will be provided in the SAP. 
 Analysis sets 
Full analysis set (FAS) 
FAS comprises all randomized patients who underwent surgery. All endpoints will be 
evaluated using FAS. 
 
Per-protocol set (PPS) 
PPS includes all patients from FAS without protocol deviations which might affect the 
evaluation of primary endpoint. The principal investigator will assess protocol non-adherence 
on a case-by-case basis. Patients with significant deviations from the study protocol will be 
excluded from PPS. 
PPS will be used for analysis of primary endpoint. 
 

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9. DATA MANAGEMENT AND QUALITY ASSURANCE 
 eCRF database  
All participants will be assigned an identification code to ensure the pseudonymization of their 
data. The investigator will maintain a subject identification list for the trial centre (subject 
identification codes with the corresponding subject names) to enable records to be identified. 
Trial data will be collected in eCRFs managed in electronic data capture system REDCap. 
Access to the database (username, password) will be granted by the study data manager, and 
the respective study staff will be trained for using it right and safely. The investigator is 
responsible for the data correctness, completeness, and filling in time. eCRF will be designed 
to generate queries on missing or unusual data in regular intervals. 
The statistician will analyse the study data in cooperation with the principal investigator. The 
data will be stored for 25 years after completion of the study and then destroyed.  
 Trial documents, medical records 
The investigator must maintain adequate and accurate records to enable the conduct of the 
trial to be fully documented. All essential paper documents are to be kept in the Investigator 
Site File (ISF) at the trial centre. Trial procedures, examinations and results must be described 
adequately in the patient’s medical records, as well.  
The sponsor, the trial site and study staff will handle the subject's personal and trial data 
according to the effective legislation regarding data protection. Any paper or electronic trial 
documents or data are confidential and must not be disclosed to the third persons. In the 
informed consent form, the participants are informed that their medical records can be provided 
only to the authorized monitors, auditors, or inspectors.  
Medical records of the subjects will be kept in a legible form for 25 years from the end of the 
clinical trial, as well as the relevant trial administrative documents at the sponsor's side. 
 Monitoring and auditing 
The trial centre will be monitored according to the Monitoring plan. The objectives of the 
monitoring are to ensure that the trial participant's safety and rights are respected, that 
accurate, valid and complete data are collected, and that the trial is conducted in accordance 
with the trial protocol, the principles of GCP and national legislation. Data in the eCRF will be 
reviewed and/or verified by the monitor during monitoring visits. Patient’s medical records will 
serve as a source document for the verification. 
The investigator agrees that the monitor will regularly visit the trial centre and will be given 
appropriate support (e.g., the access to all necessary documents incl. patient's medical 
records). A report on the progress, findings and resolution of any discrepancies will be 
prepared from each monitoring visit. The investigator undertakes to read the monitoring report 
and to ensure that any possible discrepancies are corrected. Sponsor, regulatory authority and 
ethics committees have the right to inspect/audit the trial site. The investigator undertakes to 
co-operate with the inspectors/auditors. 

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 Steering committee 
The Steering Committee is constituted by all study investigators of the NCHGDT trial. It is 
responsible for the development of the study protocol, continuous and final results 
interpretations and manuscripts preparation.  
 Medical monitoring  
All ambiguous SAE or protocol deviations will be assessed by the investigator in consultation 
with the PhV manager and medical monitor of the study.  
10. 
ETHICAL ASPECTS 
This trial will be conducted following the applicable legislation and requirements for good 
clinical practice according to the ICH E6(R2). Compliance with this standard provides public 
assurance that the rights, safety, and well-being of trial participants are protected and that the 
clinical trial data are credible. All essential trial documents and their potential amendments will 
be submitted to the relevant ethics committee and regulatory authority for approval through 
CTIS.  
 
Informed consent procedure 
Consent will be acquired according to applicable legislation. Investigator will describe and 
discuss the content and course of the study with patients who also receive written information 
about the study. Adequate time will be given for the subject or his or her legally designated 
representative to consider his or her decision to participate in the clinical trial. Investigator will 
obtain written consent from patients willing to participate in the trial. If trial subject is unable to 
sign the informed consent form because of medical condition, his or her legally designated 
representative after being duly informed of the nature of the study, may sign the consent. 
Where the subject is unable to write, consent may be given and recorded through appropriate 
alternative means in the presence of at least one impartial witness. In that case, the witness 
will sign and date the informed consent document. The subject or, where the subject is not 
able to give informed consent, his or her legally designated representative will be provided with 
a copy of the document (or the record) by which informed consent has been given. The 
informed consent will be documented.  
In case of patient´s inability to consent because of medical condition, the ability to participate 
in the study will be assessed by a medical council consisting of one independent physician 
informed of the study details and one study investigator. The informed consent has to be 
obtained from the patient as soon as possible when their medical condition improves, and they 
are able to sign the informed consent. 
 
Supervision of the informed consent procedure 
The process of obtaining informed consent from the subject, his or her legally designated 
representative or impartial witness, must always be properly documented by the investigator 
using valid forms as well as the patient's medical records. The clinical trial monitor will check 

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the process during monitoring visits. Important deviations in the process will lead to the 
termination of the patient's participation in the trial. 
11. 
PUBLICATION POLICY 
Results of this clinical trial are planned to be published in the medical literature. Any 
publications must be approved by the sponsor and meet the quality requirements for current 
clinical research publications (e.g., CONSORT statement). 
12. 
FINANCING AND INSURANCE 
NCHGDT is an investigator-initiated clinical trial. Financial resources will be provided from 
grant sources or Brno University Hospital project to support science and research. 
Investigators declare no financial or non-financial competing interest regarding the focus of 
this trial. 
Mandatory insurance of the participants is arranged. The coverage for damages emerging from 
the participation in the clinical trial will be provided according to the applicable legal 
requirements. 
 
 

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13. 
REFERENCES 
 
1. Sylvester J, Lobaz S. Fluid management. Surgery (Oxford). 2022;40(6):335-343. 
2. Salzwedel C, Puig J, Carstens A, et al. Perioperative goal-directed hemodynamic therapy based on 
radial arterial pulse pressure variation and continuous cardiac index trending reduces postoperative 
complications after major abdominal surgery: a multi-center, prospective, randomized study. Crit Care. 
2013;17:R191. 
3. Calvo-Vecino JM, Ripollés-Melchor J, Mythen MG, et al. Effect of goal-directed haemodynamic 
therapy on postoperative complications in low-moderate risk surgical patients: a multicentre randomised 
controlled trial (FEDORA trial). Br J Anaesth. 2018;120:734–44. 
4. Jessen MK, Vallentin MF, Holmberg MJ, Bolther M, Hansen FB, Holst JM, Magnussen A, Hansen 
NS, Johannsen CM, Enevoldsen J, Jensen TH, Roessler LL, Lind PC, Klitholm MP, Eggertsen MA, 
Caap P, Boye C, Dabrowski KM, Vormfenne L, Høybye M, Henriksen J, Karlsson CM, Balleby IR, 
Rasmussen MS, Pælestik K, Granfeldt A, Andersen LW. Goal-directed haemodynamic therapy during 
general anaesthesia for noncardiac surgery: a systematic review and meta-analysis. Br J Anaesth. 
2022;128(3):416-433. 
5. Dushianthan A, Knight M, Russell P, Grocott MP. Goal-directed haemodynamic therapy (GDHT) in 
surgical patients: systematic review and meta-analysis of the impact of GDHT on post-operative 
pulmonary complications. Perioper Med (Lond). 2020;9:30.  
6. Kaufmann T, Clement RP, Scheeren TWL, Saugel B, Keus F, van der Horst ICC. Perioperative goal-
directed therapy: A systematic review without meta-analysis. Acta Anaesthesiol Scand. 
2018;62(10):1340-1355.  
7. Saugel B, Thomsen KK, Maheshwari K. Goal-directed haemodynamic therapy: an imprecise umbrella 
term to avoid. Br J Anaesth. 2023;130(4):390-393. 
8. Picard J, Bedague D, Bouzat P, Ollinet C, Albaladejo P, Bosson JL, Payen JF. Oesophageal Doppler 
to optimize intraoperative haemodynamics during prone position. A randomized controlled trial. Anaesth 
Crit Care Pain Med. 2016;35(4):255-60.  
9. Wongtangman K, Wilartratsami S, Hemtanon N, Tiviraj S, Raksakietisak M. Goal-Directed Fluid 
Therapy Based on Pulse-Pressure Variation Compared with Standard Fluid Therapy in Patients 
Undergoing Complex Spine Surgery: A Randomized Controlled Trial. Asian Spine J. 2022;16(3):352-
360.   
10. Abdelhamid B, Matta M, Rady A, Adel G, Gamal M. Conventional fluid management versus 
plethysmographic variability index-based goal directed fluid management in patients undergoing spine 
surgery in the prone position - a randomised control trial. Anaesthesiol Intensive Ther. 2023;55(3):186-
195.  
11. Andrzejewska A, Miegoń J, Zacha S, Skonieczna-Żydecka K, Jarosz K, Zacha W, Biernawska J. 
The Impact of Intraoperative Haemodynamic Monitoring, Prediction of Hypotension and Goal-Directed 
Therapy on the Outcomes of Patients Treated with Posterior Fusion Due to Adolescent Idiopathic 
Scoliosis. J Clin Med. 2023;12(14):4571.  
12. Luo J, Xue J, Liu J, Liu B, Liu L, Chen G. Goal-directed fluid restriction during brain surgery: a 
prospective randomized controlled trial. Ann Intensive Care. 2017;7(1):16. 

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13. Anetsberger A, Gempt J, Blobner M, Ringel F, Bogdanski R, Heim M, Schneider G, Meyer B, Schmid 
S, Ryang YM, Wostrack M, Schneider J, Martin J, Ehrhardt M, Jungwirth B. Impact of Goal-Directed 
Therapy on Delayed Ischemia After Aneurysmal Subarachnoid Hemorrhage: Randomized Controlled 
Trial. Stroke. 2020;51(8):2287-2296.   
14. Wu J, Ma Y, Wang T, Xu G, Fan L, Zhang Y. Goal-directed fluid management based on the auto-
calibrated arterial pressure-derived stroke volume variation in patients undergoing supratentorial 
neoplasms surgery. Int J Clin Exp Med. 2017;10(2):3106-3114.  
15. Kim N, Lee JH, Kim DH, Choi KW, Kim E, Choi SH. Effects of goal-directed fluid management with 
0.9% normal saline on metabolic acidosis in patients undergoing brain surgery: a prospective and 
randomized-controlled study. Int J Clin Exp Med. 2019;12(4):3994-4002. 
16. Sivakumar S, Lazaridis C. Bioreactance-Based Noninvasive Fluid Responsiveness and Cardiac 
Output Monitoring: A Pilot Study in Patients with Aneurysmal Subarachnoid Hemorrhage and Literature 
Review. Crit Care Res Pract. 2020;2020:2748181. doi: 10.1155/2020/2748181.  
17. Hrdy O, Duba M, Dolezelova A, Roskova I, Hlavaty M, Traj R, Bönisch V, Smrcka M, Gal R. Effects 
of goal-directed fluid management guided by a non-invasive device on the incidence of postoperative 
complications in neurosurgery: a pilot and feasibility randomized controlled trial. Perioper Med (Lond). 
2023;12(1):32. doi: 10.1186/s13741-023-00321-3.  
18. 
Saugel B, Sessler DI. Perioperative Blood Pressure Management. Anesthesiology. 
2021;134(2):250-261. doi: 10.1097/ALN.0000000000003610. 
 
 
 
 
 

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14. 
SUPPLEMENTS/APPENDICES 
 
APPENDIX A 
AESI definitions 
 
Acute kidney Injury 
Defined 
according 
to 
Kidney 
Disease 
Improving 
Global 
Outcomes 
(KDIGO) 
guidelines: 
 
Stage 1: serum creatinine 1.5–1.9 times 
baseline value within 7 days or ≥27 µmol l-1 (0.3 
mg dl-1) increase within 48 h; urine output ≤0.5 
ml kg-1 h-1 for 6–12 h 
 
Stage 2: serum creatinine 2.0–2.9 times 
baseline value within 7 days; urine output ≤0.5 
ml kg-1 h-1 for 12 h 
 
Stage 3: serum kreatinine 3.0 times baseline 
within 7 days or increase in serum creatinine to 
≥354 µmol l-1 (≥4.0 mg.dl1 with an acute rise of 
> 44 mmol l-1 (0.5 mg/dl-1) or initiation of renal 
replacement therapy or in patients < 18 years, 
decrease in eGFR to < 35 ml min-1 per 1.73m2; 
urine output ≤0.3 ml kg1 h-1 for 24 h or anuria 
for 12 h 
Acute Respiratory Distress Syndrome (ARDS) 
The Berlin definition of Respiratory Distress 
Syndrome: 
 
Timing: Within one week of a known clinical 
insult or new or 
worsening respiratory 
symptoms and 
 
Chest imaging: Bilateral opacities not fully 
explained by effusions, lobar/lung collapse or 
nobles and 
  
Origin of oedema: Respiratory failure not fully 
explained by cardiac failure or fluid overload. 
Need 
objective 
assessment 
(e.g. 
echocardiography) to exclude hydrostatic 
oedema if no risk factor is presented and 
 
Oxygenation 
disorder: 
mild: 
PaO2:FIO2 
between 26.7 and 40.0 kPa (200–300mmHg) 
with PEEP or CPAP ≥5 cmH2O. Moderate: 
PaO2:FIO2 between 13.3 and 26.6 kPa (100–
200 mmHg) with PEEP ≥5 cmH2O. Severe: 
PaO2:FIO2  ≤13.3 kPa (100mmHg) with PEEP 
≥5 cmH2O 
Arrhythmia 
Defined as electrocardiograph (ECG) evidence 
of cardiac rhythm disturbance.  
 
Severity grading: * 
Cardiac arrest 
Cessation of cardiac mechanical activity, as 
confirmed by the absence of signs of 
circulation. 
Cardiogenic pulmonary oedema 
Defined as evidence of fluid accumulation in 
the alveoli due to poor cardiac function. 
 
Severity grading: * 
Deep vein thrombosis (DVT) 
A new blood clot or thrombus within the venous 
system.  

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Appropriate 
diagnostic 
tests 
include 
ultrasound, 
venography, 
CT 
or 
MRI 
venography. Plasma D-dimer measurement is 
not recommended as a diagnostic test in the 
first three weeks following surgery. 
 
Severity grading: * 
Pulmonary embolism (PE) 
A new blood clot or thrombus within the 
pulmonary arterial system.  
Gastrointestinal bleed 
Clinical or endoscopic evidence of blood in the 
gastrointestinal tract. 
 
Severity grading: * 
Infection, source uncertain 
Infection where there is strong clinical 
suspicion of infection but the source has not 
been confirmed because clinical information 
suggests more than one possible site, meeting 
two or more of the following criteria: core 
temperature < 36°C or >38°C; white cell count 
>12×109 l-1 or < 4×109 l-1, respiratory rate >20 
breaths per minute or PaCO2 < 4.7 kPa 
(35mmHg); pulse rate >90 beats per minute 
 
Severity grading: * 
Laboratory confirmed bloodstream infection 
Infection which meets at least one of the 
following criteria which should not be related to 
infection at another site: 
1. Patient 
has 
a 
recognised 
pathogen 
cultured from one or more blood cultures 
and the organism cultured from blood is not 
related to an infection at another site. 
2. Patient has at least one of the following 
signs or symptoms: fever >38°C, chills or 
hypotension, and at least one of the 
following:  
a. Common 
skin 
contaminant 
cultured from two or more blood 
cultures 
drawn 
on 
separate 
occasions 
b. Common 
skin 
contaminant 
cultured from at least one blood 
culture from a patient with an 
intravascular 
line, 
and 
the 
physician institutes appropriate 
antimicrobial therapy 
c. Positive blood antigen test. 
Severity grading: * 
Myocardial infarction 
Defined 
as 
increase 
in 
serum 
cardiac 
biomarker values (preferably cardiac troponin) 
with at least one value above the 99th 
percentile upper reference limit and at least 
one of the following criteria: symptoms of 
ischaemia; new or presumed new significant 
ST segment or T wave ECG changes or new 
left bundle branch block; development of 
pathological Q waves on ECG; radiological or 

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echocardiographic evidence of new loss of 
viable myocardium or new regional wall motion 
abnormality; identification of an intracoronary 
thrombus at angiography or autopsy. 
 
Severity grading: * 
Pneumonia 
Definition: 
Two 
or 
more 
serial 
chest 
radiographs with at least one of the following 
(one radiograph is sufficient for patients with no 
underlying pulmonary or cardiac disease): 
 
(1) new or progressive and persistent infiltrates 
(2) consolidation 
(3) cavitation;  
at least one of the following: 
(1) fever (>38°C) with no other recognised 
cause 
(2) leucopaenia (white cell count < 4 × 109 l-1) 
or leucocytosis (white cell count >12 × 109 l-1) 
(3) for adults >70 years old, altered mental 
status with no other recognised cause;  
and at least two of the following: 
(1) new onset of purulent sputum or change in 
character of sputum, or increased respiratory 
secretions, 
or 
increased 
suctioning 
requirements 
(2) new onset or worsening cough, or 
dyspnoea, or tachypnoea 
(3) rales or bronchial breath sounds 
(4) worsening gas exchange (hypoxaemia, 
increased oxygen requirement, increased 
ventilator demand). 
Severity grading: * 
Paralytic ileus 
Failure to tolerate solid food or defecate for 
three or more days after surgery. 
Severity grading: * 
Postoperative haemorrhage 
Blood loss within 72 h after the start of surgery 
which would normally result in transfusion of 
blood. 
 
Severity 
grading: 
Mild: 
Not 
applicable. 
Moderate: Complication which does not 
usually result in permanent harm or functional 
limitation. Usually requires clinical treatment. 
Severe: Results in significant prolongation of 
hospital stay and/or permanent functional 
limitation or death. Almost always requires 
clinical treatment. 
Stroke 
An embolic, thrombotic or haemorrhagic 
cerebral event with persistent residual motor, 
sensory 
or 
cognitive 
dysfunction 
(e.g. 
hemiplegia, hemiparesis, aphasia, sensory 
deficit, impaired memory). 
Severity grading: * 
Brain oedema  
 
 
 
 
Brain oedema confirmed on CT or MRI scan. 
Severity Grading: * 
Surgical site infection (superficial) 
A superficial incisional surgical site infection is 
defined as one which meets the following 
criteria: 

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(1) Infection occurs within 30 days after surgery 
and 
(2) Involves only skin and subcutaneous tissue 
of the incision and 
(3) The patient has at least one of the following: 
(a) 
purulent 
drainage 
from 
the 
superficial incision 
(b) 
organisms 
isolated 
from 
an 
aseptically obtained culture of fluid or tissue 
from the superficial incision 
(c) at least one of the following 
symptoms or signs of infection: pain or 
tenderness, localised swelling, redness or 
heat, and superficial incision is deliberately 
opened by surgeon and is culture positive or 
not cultured. A culture-negative finding does 
not meet this criterion. 
(d) diagnosis of an incisional surgical 
site infection by a surgeon or attending 
physician. 
Severity grading: * 
Surgical site infection (deep) 
A deep incisional surgical site infection as one 
which meets the following criteria: 
 
(1) Infection occurs within 30 days after surgery 
if no implant is left in place or 1 year if implant 
is in place. 
(2) Involves deep soft tissues (e.g. fascial and 
muscle layers) of the incision. 
(3) The patient has at least one of the following: 
(a) purulent drainage from the deep 
incision 
but 
not 
from 
the 
organ/space 
component of the surgical site 
(b) a deep incision spontaneously 
dehisces or is deliberately opened by a 
surgeon and is culture-positive or not cultured 
when the patient has at least one of the 
following symptoms or signs: fever (>38°C), or 
localised pain or tenderness. A culture-
negative finding does not meet this criterion. 
(c) an abscess or other evidence of 
infection involving the deep incision is found on 
direct examination, during surgery, or by 
histopathological or radiological examination 
(d) diagnosis of an incisional surgical 
site infection by a surgeon or attending 
physician. 
Severity grading: * 
Surgical site infection (organ/space) 
Infection which involves any part of the body 
excluding the fascia or muscle layers and 
meets the following criteria: 
 
(1) Infection occurs within 30 days after 
surgery. 
(2) The infection appears to be related to the 
surgical procedure and involves any part of the 
body, excluding the skin incision, fascia or 

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muscle layers opened or manipulated during 
the operative procedure. 
(3) The patient has at least one of the following: 
(a) purulent drainage from a drain that 
is placed through a stab wound into the 
organ/space 
(b) 
organisms 
isolated 
from 
an 
aseptically obtained culture of fluid or tissue in 
the organ/space 
(c) an abscess or other evidence of 
infection involving the organ/space that is 
found 
on 
direct 
examination, 
during 
reoperation 
or 
by 
histopathological 
or 
radiological examination 
(d) diagnosis of an organ/space 
surgical site infection by a surgeon or attending 
physician. 
Severity grading: * 
Urinary tract infection 
A positive urine culture of ≥105 colony forming 
units ml-1 with no more than two species of 
micro-organisms, and with at least one of the 
following symptoms or signs: fever (>38°C), 
urgency, 
frequency, 
dysuria, 
suprapubic 
tenderness, costovertebral angle pain or 
tenderness with no other recognised cause. 
Each of these criteria should be identified 
within a 24-h period. 
Severity grading: * 
 
*Severity grading:  
 
Mild: Results in only temporary harm and would not usually require specific clinical treatment. 
Moderate: More serious complication but one which does not usually result in permanent harm or 
functional limitation. Usually requires clinical treatment. 
Severe: Results in significant prolongation of hospital stay and/or permanent functional limitation or 
death. Almost always requires clinical treatment.