A Pilot Study to Test Benefits of Drinking Clear Fluids Until Called to the Operating Room in Adult Surgical Patients
Phase: NA
Conditions: Anesthesia, Thirst; Due to Deprivation of Water, Aspiration
Sponsor: Wuerzburg University Hospital

 
 
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Investigator 
Dr. med. Tobias Eberhard Haas 
Department of Anaesthesiology, Intensive Care, 
Emergency and Pain Medicine 
University Hospital Würzburg 
Oberdürrbacher Str. 6 
97080 Würzburg, Germany 
 
Biometry 
Prof. Dr. Peter U. Heuschmann 
Institute of Clinical Epidemiology and Biometry, 
University of Würzburg, 
Josef-Schneider-Straße 2, 
97080 Würzburg, Germany 
 
 
Sponsor 
 
University Hospital Würzburg, 
Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, 
Oberdürrbacher Str. 6, 97080 Würzburg, Germany 
 
 
 
Date: 24.06.2024 
Version: 1.0 
 
 
 
 
 
 
 
 
 
 
 
 
https://clinicaltrials.gov (NCT06253052) 
Trial Protocol
 
A Pilot study to test benefits of drinking clear 
fluids until called to the operating room in adult 
surgical patients 
 
[HYDRATE-Trial] 

 
 
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TABLE OF CONTENTS 
1 
GENERAL INFORMATION ...................................................................................... 3 
1.1 
Administrative Information ........................................................................................ 3 
1.2 
Synopsis ................................................................................................................... 3 
2 
INTRODUCTION ...................................................................................................... 8 
2.1 
Medical Background ................................................................................................. 8 
2.2 
Choice of Comparators ............................................................................................. 9 
2.3 
Study objectives ..................................................................................................... 10 
2.4 
Trial design ............................................................................................................. 10 
3 
METHODS: PARTICIPANTS, INTERVENTIONS, OUTCOMES ............................ 10 
3.1 
Study Setting .......................................................................................................... 10 
3.2 
Interventions ........................................................................................................... 10 
3.3 
Adherence .............................................................................................................. 12 
3.4 
Concomitant Care ................................................................................................... 12 
3.5 
Outcomes ............................................................................................................... 12 
3.6 
Participant Timeline and Individual Study Visits ...................................................... 13 
4 
METHODS: ASSIGNMENT OF INTERVENTIONS ................................................ 15 
4.1 
Allocation ................................................................................................................ 15 
4.2 
Blinding ................................................................................................................... 15 
5 
METHODS: DATA COLLECTION, MANAGEMENT, ANALYSIS .......................... 15 
5.1 
Data collection Methods.......................................................................................... 15 
5.2 
Retention ................................................................................................................ 15 
5.3 
Data Management .................................................................................................. 15 
5.4 
Endpoints ............................................................................................................... 16 
5.5 
Sample Size ........................................................................................................... 16 
5.6 
Statistical Methods .................................................................................................. 16 
6 
METHODS: HARMS/ ADVERSE EVENTS (AE/SAE) ............................................ 16 
6.1 
Definition of (serious) adverse events ..................................................................... 17 
6.2 
Documentation of (serious) adverse events ............................................................ 17 
6.3 
Other Safety Relevant Issues ................................................................................. 17 
6.4 
Therapeutic Procedures.......................................................................................... 18 
6.5 
Dealing with Pregnancy .......................................................................................... 18 
7 
ETHICS AND DISSEMINATION ............................................................................. 18 
7.1 
GCP-Statement ...................................................................................................... 18 
7.2 
Initial Submission .................................................................................................... 18 
7.3 
Protocol Amendments ............................................................................................ 18 
7.4 
Data protection and Confidentiality ......................................................................... 19 
8 
ADMINISTRATIVE AGREEMENTS ....................................................................... 20 
8.1 
Adherence to the Protocol ...................................................................................... 20 
8.2 
Funding and Insurance ........................................................................................... 20 
8.3 
Publication Policy and Registration ......................................................................... 20 
9 
REFERENCES ....................................................................................................... 20 
10 
APPENDIX ............................................................................................................. 23 
10.1 
Classification of Adverse Events ............................................................................. 23 
11 
PROTOCOL SIGNATURES AND AGREEMENT ................................................... 25 
 
 

 
 
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1 GENERAL INFORMATION 
1.1 Administrative Information 
1.1.1 Responsible Parties 
Sponsor 
University Hospital Würzburg, Institution incorporated 
under public law, represented by the Medical Director 
Josef-Schneider-Straße 2, 97080 Würzburg, Germany  
 
Authorised representative of the sponsor: 
Prof. Dr. med. Patrick Meybohm 
 
University Hospital Würzburg, 
Department 
of 
Anaesthesiology, 
Intensive 
Care, 
Emergency and Pain Medicine, 
Oberdürrbacher Str. 6, 
97080 Würzburg, Germany 
Tel: +49 931 201-30001 
E-Mail: meybohm_p@ukw.de 
Data Management 
and 
Biometry 
Prof. Dr. Peter U. Heuschmann
 
Institute of Clinical Epidemiology and Biometry, 
University of Würzburg, 
Josef-Schneider-Straße 2, 
97080 Würzburg, Germany 
1.1.2 Trial/Study Registration 
The trial will be registered on clinicaltrials.gov before enrolment of the first site. Wherever 
words denoting a specific gender are used in this protocol, they are intended to apply equally 
to all persons without regard to gender. 
1.2 Synopsis 
Title 
A pilot study to test benefits of drinking clear fluids until called to 
the operating room in adult surgical patients. 
Short title 
HYDRATE-Study 
Indication 
Patients ≥ 18 years of age undergoing surgery without an 
indication for rapid sequence induction.  
Primary end point 
Primary efficacy endpoint: 
 
Patient thirst (No; Yes, moderate; Yes, severe) 
Endpoint will be measured prior to anaesthesia induction. 
Secondary end points 
Key secondary endpoints:  
We will pilot test the intervention to demonstrate its acceptability 
and feasibility and to identify target outcomes for further trials. 
 
Piloting for feasibility assessment: 
 
Total number of protocol deviations per group 
o 
Outcome assessment successfully blinded 
o 
Real fluid fasting time is less than allocated fluid 
fasting time 
 
Fluid fasting time 
 

 
 
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Piloting for future power calculations: 
 
Richmond Agitation Sedation Scale (RASS)  
 
Confusion Assessment Method for the Intensive Care Unit 
(CAM-ICU) 
 
Headache 
 
Vital signs (delta heart rate, delta blood pressure) 
 
Cumulative Vasopressor dose within 15 min after 
anaesthesia induction 
 
Blood glucose level 
 
Number of attempts for placing a peripheral intravenous 
catheter 
 
Postoperative nausea and vomiting (PONV) 
 
Safety Endpoints: 
 
Unplanned intensive/intermediate care unit stay due to 
respiratory complications 
 
Confirmed bronchopulmonary aspiration 
 
Death within observation period 
Trial design 
The study is a prospective, single centre, outcome assessor 
blinded, controlled randomised clinical trial (RCT) with 3 arms. 
Trial population 
Inclusion criteria on the individual level: Patients ≥ 18 years of age 
scheduled for surgery under anaesthesia care (general anaesthesia, 
regional 
anaesthesia, 
combined 
anaesthesia 
or 
monitored 
anaesthesia care) with an ASA physical status classification I-III. 
Exclusion criteria: Absolute and relative indication for rapid 
sequence induction, dysphagia, renal replacement therapy, fluid 
restriction therapy, pregnancy, expected need for postoperative 
mechanical ventilation and prior enrolment in this trial. 
Sample size 
n = 174 (55 per group +5% drop-outs = 58 per group) 
Study Procedures 
Group 1 (control) - Usual care: Fasting instructions as given by 
anaesthesiologist according to national guidelines (6 h solid meal 
and thick liquids, 2 h clear fluids).  
Group 2 (intervention) - Instructed guideline adherence: As per 
“Usual care”. In addition, the operating room schedule is closely 
monitored and the patient will be visited to be supported and 
encouraged in drinking clear fluids freely until 2 h before the 
anticipated beginning of anaesthesia. 
Group 3 (intervention) - Experimental intervention: As per 
“instructed guideline adherence” with the difference that the patient 
will be educated and encouraged to drink up to 200 ml clear fluids 
between 2 h prior to anaesthesia and the call to operation room. 
From this concludes that patients are allowed to drink up to 100 ml 
clear fluids every 1 h the anaesthesia is postponed. 
Follow-up per patient: 2 h after discharge from the operating room 
(up to 48 h e.g. in case of bronchopulmonary aspiration). 
 
Biometry 
Analyses will be intention-to-treat. The primary endpoint will be 
analysed by standard methods of descriptive statistics, namely chi-
square test. 
The treatment effect will be quantified on the odds ratio scale with 
two-sided 95% confidence intervals provided. Secondarily, also 
point estimates and confidence intervals for the rate difference 
and the relative risk will be provided. 
 
The overall trial will have 80% power (alpha=0.05) 

 
 
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Trial Duration 
Duration of intervention: On the day of scheduled surgery until call 
to the operating room. 
Individual trial duration: From the day of scheduled surgery until 
up to 2 h after discharge from the operating room. Follow-up might 
be postponed up to 48 h e.g. in case of bronchopulmonary 
aspiration. 
Planned recruitment period: 3 months 
The trial formally starts with the treatment of the first patient (FPI = 
first patient in), and the formal end of the study is the last follow-up 
visit of the last patient included (LPO = last patient out). 
The total study duration will be 3 months.
 
 
 
Fig. 1: Possible courses through the study 
 

 
 
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1.2.1 Schedule of Assessments and Procedures 
Examinations
Screening
Intervention
Prior to
anaesthesia
After
induction 
Follow up
  
28 days 
up 
to 0 days
before 
surgery 
On the day of 
surgery until 
call to the 
operating 
room 
Immediately
before 
anaesthesia
induction 
Immediately 
after 
anaesthesia 
induction 
2 h
(±30 min) 
after 
procedurea 
Visit 
V1 
V2 
V3 
V4 
V5 
Inclusion criteria 
X 
  
  
  
  
Exclusion criteria 
X 
  
  
  
  
Informed consent 
X 
  
  
  
  
Medical historyb 
X 
  
  
  
  
Baseline 
assessments 
X 
  
  
  
  
Registration 
X 
  
  
  
  
Demographics 
X 
  
  
  
  
Randomisation 
X 
  
  
  
  
Intervention 
  
X 
  
  
  
Fasting time 
  
  
(X)c 
  
X 
IV-catheter
placement 
  
  
X 
  
  
Patient satisfaction 
  
  
X 
  
X 
Blood glucose level 
  
  
X 
(X)d 
  
Vital signs 
  
  
X 
X 
  
Use of vasopressors   
  
  
X 
  
Bronchopulmonary
aspiration 
  
  
  
X 
X 
Headache 
  
  
X 
  
X 
PONV 
  
  
  
  
X 
RASS + CAM-ICU 
  
  
  
  
X 
Blinding successful 
  
  
X 
X 
X 
aFor general anaesthesia this is 2 h after extubation. For regional anaesthesia this is 2 h after skin 
suture. Parts of Follow up might be postponed up to 48 h e.g. if bronchopulmonary aspiration is to be 
confirmed. 
bThe premedication visit will be added to the study documentation to record the inclusion and 
exclusion criteria. 
cFluid fasting time must be greater than 30 minutes at anaesthesia induction. The actual fasting time 
will be assessed at the end of V5 to ensure outcome assessor blinding.dOnly if not done at V4. 

 
 
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1.2.2 Study Flow Chart 
 

 
 
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2 INTRODUCTION 
2.1 Medical Background 
Preoperative fasting guidelines aim to minimize the risk of gastrointestinal regurgitation and 
bronchopulmonary aspiration with international guidelines recommending clear fluid intake up 
to 2 h and intake of solid foods and thick liquids up to 6 h prior to anaesthesia induction1-4. 
Perioperative bronchopulmonary aspiration events are rare5,6 and full recovery is typical6,7. 
Even when fasting guidelines are not followed, perioperative bronchopulmonary aspiration rate 
has previously been reported as low as 0 % in low-risk populations such as patients undergoing 
ambulatory cataract surgery8 or procedures other than endoscopy performed with procedural 
sedation5. 
 
Already three decades ago the adverse consequences of “Nil per os” (NPO) from midnight”-
fasting practices have been recognized. Compelling research efforts demonstrating the benefit 
of allowing free clear fluid intake until 2-3 h preoperatively without increasing 
bronchopulmonary aspiration rates eventually resulted in changes to international 
guidelines9,10,51. While fasting guidelines have changed, extensive preoperative fasting 
remains common clinical reality11-14. Recently, new discussions have started debating further 
liberation of preoperative fluid intake restrictions in order to avoid dehydration and improve 
patient comfort15-19. 
2.1.1 Dehydration 
Contradicting to “primum non nocere” the current practise may harm patients due to 
dehydration. Dehydration has been shown to worsen the outcome of strokes 20, raises the risk 
of infection, may prolong length of stay21, lead to thrombosis, ACS22,23 or acute kidney injury24. 
Dehydration aggravates pain in general and is discussed as a risk factor for post-lumbar 
puncture headache from iatrogenic spinal fluid leak 25. 
Parenteral hydration may be considered as a solution, but the risk of infection increases with 
the time after IV-catheter insertion. Besides the typical risks and complications of an IV-
catheter it also reduces patient mobility and contributes to patient stress. This contradicts 
modern treatment principles like Fast-Track. Furthermore, parenteral hydration does not 
alleviate dry mouth. 
The first principle of 2017 NICE (National Institute of Health and Care Excellence) 
Recommendations is “Provide intravenous (IV) fluid therapy only for patients whose needs 
cannot be met by oral or enteral routes […]”. NICE further argues that a significant number of 
hospitalised patients were dying as a result of infusion of too much or too little fluid. 26  
According to NICE warning signs for dehydration include but are not limited to: 
 
systolic blood pressure is less than 100 mmHg 
 
heart rate is more than 90 beats per minute 
2.1.2 Gastric contents 
Over the last decade, point-of-care gastric ultrasound has advanced into a well-established 
and validated tool for evaluation of gastric content27,28 in research as well as clinical settings. 
Gastric ultrasound may guide the assessment of bronchopulmonary aspiration risk and enable 
risk-adapted clinical decision making29,30. 
Preoperative fasting aims to reduce residual gastric volume and increase pH, because higher 
bronchopulmonary aspiration volume and acidity (e.g. pH < 2.5) are associated with higher 
mortality in animal models31,32. 
This is primarily of relevance for solid food, because drinking 200 ml water raises the gastric 
pH above pH 4 for a short period of time, as water not only dilutes gastric acid but also has a 
buffering capacity33. The time it takes for oral intake to move on from the stomach depends 

 
 
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largely on composition, calories and volume of the content. This is especially true if pathologies 
causing delay in gastric emptying are not present34. Half of ingested water volume is emptied 
from the stomach in about 10 min with complete clearance at around 40 min and 80% 
clearance at 30 min as demonstrated in various studies utilizing isotope activity, MRI imaging 
as well as gastric ultrasound to examine gastric emptying physiology35-37. 
Adherence to NPO does not automatically result in a completely empty stomach. A residual 
gastric volume of up to 1.8 ml/kg has been demonstrated among patients undergoing elective 
cholecystectomy and healthy volunteers38,39. In a study examining gastric emptying of water, 
there was no significant difference of emptying times or residual baseline gastric volume 
between individuals who remained NPO within 4 h prior to the experiment and those allowed 
water intake40. In accordance with the volume reported in a fasted state, a residual gastric 
volume above > 1.5 ml/kg has been proposed to indicate higher risk of perioperative 
bronchopulmonary aspiration39. 
2.1.3 Liberal fasting regime in paediatrics 
Elaborate quality improvement initiatives in paediatric anaesthesia have been successful in 
their efforts to reduce fluid fasting among children13,14,41, but fear of delay or cancellation of the 
procedure in case of fluid intake poses a substantial challenge. In some reports in the 
paediatric population, clear fluid intake was allowed until called to the operating room42-44 
without 
observing 
differences 
in 
bronchopulmonary 
aspiration 
events 
or 
cancellation/postponement of procedures45. Multiple renowned anaesthesia societies have 
issued statements endorsing more liberal oral fluid intake preoperatively in paediatric 
anaesthesia, like “6-4-1” or “6-4-0” fasting regimes46-48.  
 
Level of similar evidence in the adult population is low12. There is no plausible argument why 
adults should be different than children and teenagers in this matter. In fact, reported 
bronchopulmonary aspiration rates are higher among children6. Of note, recommendations of 
the Scandinavian Society of Anaesthesiology and Intensive Care Medicine from 2005 permit 
adults to drink up to 150 ml and children up to 75 ml of clear fluids until 1 hour prior to 
anaesthesia3. 
2.2 Choice of Comparators 
2.2.1 Hypothesis 
We hypothesize that - compared to standard practice - allowing Patients ≥ 18 years of age 
undergoing surgery under anaesthesia care to drink clear fluids up to a volume of 200 ml 
between 2 h prior to anaesthesia and the call to operation room (approximately 30 min prior to 
anaesthesia induction) will decrease patient thirst and increase patient satisfaction. 
2.2.2 Risk-Benefit Considerations 
Besides the change in preoperative fluid intake, all patients will receive standard perioperative 
care. 
 
Taking the available data into account it is unlikely for patients in the intervention group to have 
a substantially higher risk of bronchopulmonary aspiration or a different severity of 
bronchopulmonary aspiration complications. 
Instead, they will be much less likely to experience excessive preoperative fasting durations, 
which may lead to preoperative dehydration and subsequently contribute to hypotension after 
anaesthesia induction49,50. This will furthermore improve patient discomfort characterized by 
increased hunger, thirst, anxiety, sadness, pain, stress and nausea51-53 and may even 
positively influence early postoperative delirium11 as well as the length of the hospital stay54. 
 

 
 
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In paediatrics and labouring women55 as well as for adults 51,56-58 allowing clear fluid intake until 
call to the operating room was already successfully implemented without an increase in 
bronchopulmonary aspirations being reported. 
2.2.3 Significance 
The growing practise of preoperative fluid consumption ad libitum needs a careful risk-benefit-
consideration. It is therefore necessary to assess the benefits. This may pave the way to lift 
the burden of preoperative thirst from millions of patients yet to come, as the intervention is 
freely available und rapidly translatable into clinical practice. 
2.3 Study objectives 
2.3.1 Primary Objective 
To evaluate if allowing patients to drink clear fluids until call to the operating room prior to 
anaesthesia induction will improve patient thirst compared to allowing clear fluid intake up to 
2 h prior to anaesthesia induction. 
2.3.2 Secondary Objective 
We will pilot test the intervention to demonstrate its acceptability and feasibility - in particular 
we test if the outcome assessment is blindable. The secondary outcomes aim to identify targets 
for further trials. 
2.4 Trial design 
2.4.1 Trial Design 
The study is an outcome assessor blinded randomised trial (RCT) with three parallel treatment 
arms. 
3 METHODS: PARTICIPANTS, INTERVENTIONS, OUTCOMES 
3.1 Study Setting 
The study will be conducted at the University Hospital Würzburg enrolling in- and outpatients. 
3.2 Interventions 
Group 1 (control) - Usual care: Fasting instructions as given by anaesthesiologist according to 
national guidelines (6 h solid meal and thick liquids, 2 h clear fluids). 
Group 2 (intervention) - Instructed guideline adherence: As per “Usual care”. In addition, the 
patients will be visited to support and encourage them in drinking clear fluids freely until 2 h 
before the anticipated anaesthesia induction. 
Group 3 (intervention) - Experimental intervention: As per “instructed guideline adherence” 
with the difference that patients are educated and encouraged to drink up to 200 ml clear fluids 
between 2 h prior to anaesthesia induction and the call to operation room. Education and 
information dissemination measures will be taken. Patients receive a container of known 
volume (e.g. cups, glasses, mugs, bottles with volume marks). From this concludes that 
patients are allowed to drink up to 100 ml clear fluids every 1 h anaesthesia induction is 
postponed. Patients may vary their fluid intake to meet this stipulation and their personal needs 

 
 
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e.g. by drinking 100 ml every hour or any other way that does not surpass 200 ml per 2 h (see 
Fig. 1). 
3.2.1 Inclusion criteria 
Patients may only be allowed to drink clear fluids up to call to operating room if they fulfill all 
the following criteria: 
1. Adult patients (≥ 18 years) 
2. Undergoing surgery under anaesthesia care: general anaesthesia, regional anaesthesia, 
combined anaesthesia or monitored anaesthesia care. 
3. ASA physical status classification I-III 
The proportion of patients undergoing general or combined anaesthesia is aimed to exceed 
75%. 
3.2.2 Exclusion Criteria 
Individual patients may only be allowed to drink clear fluids up to call to operating room if they 
fulfill none of the following criteria: 
1. Absolute indication for rapid sequence induction including but not limited to: 
a. Bowel obstruction including ileus 
b. Stricture and oesophageal disorders including achalasia 
c. Recent polytrauma or trauma of the upper gastrointestinal tract 
d. Acute abdomen/peritonitis including active gastrointestinal bleeding 
2. Relative indication for (modified) rapid sequence induction includes, but is not limited to: 
a. Symptomatic gastroesophageal reflux disease, independent of food intake and 
persistent under medical treatment (PPI) 
b. Hiatus hernia or upside down stomach 
c. Upper gastrointestinal tumour 
d. History of upper gastrointestinal surgery (oesophageal, gastric, duodenum, 
pancreatic)  
e. Medically confirmed gastroparesis 
f. Severe obesity, defined as body mass index ≥ 40 kg/m2 
3. Dysphagia 
4. Renal replacement therapy 
5. Fluid restriction therapy 
6. Pregnancy 
7. Expected need for postoperative mechanical ventilation  
8. Prior enrolment in this trial. 

 
 
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3.3 Adherence 
3.3.1 Compliance 
Physicians will retain the right to assign patients to a fasting regime as per national guideline 
and/or postpone anaesthesia induction if they are concerned for patient safety due to 
unforeseen risk factors for bronchopulmonary aspiration. 
3.4 Concomitant Care 
As shown by Rüggeberg et al.56, allowing patients fluid intake until call to the operating room 
on its own does not reduce fasting times. Only if it is combined with encouraging the patients 
to drink the fasting time decreases signifficantly. We therefore estimate the effects of 
contamination bias to be small. To reduce the risk of timing bias the day-of-surgery-visit of the 
study staff to reencourage drinking is aimed to take place 2 h before anaesthesia is scheduled. 
3.4.1 Overdose and Abuse 
To ensure minimal risk of bronchopulmonary aspiration the attending anaesthesiologist retains 
the right to postpone anaesthesia induction, which is warranted in cases, where the patient 
exceeds the 200 ml fluids intake in the last 2 h or has consumed solid foods less than 6 h 
before anaesthesia induction. 
3.5 Outcomes 
3.5.1 Primary Outcome 
The primary efficacy outcome is adapted from item #3 of the Bauer satisfaction questionnaire 
and measured prior to anaesthesia induction of anaesthesia: Have you had the following today: 
Thirst (No/ Yes, moderate/ Yes, severe) 
3.5.2 Secondary Outcome 
Piloting for feasibility assessment: 
1. Total number of protocol deviations per group 
a. Outcome assessment successfully blinded 
b. Violation of fluid fasting time and fluid fasting time in general 
 
Piloting for future power calculations: 
2. Richmond Agitation Sedation Scale (RASS)  
3. Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) 
4. Headache 
5. Vital signs (delta HF, delta RR) 
6. Cumulative vasopressor dose within 15 min after anaesthesia induction 
7. Blood glucose level 
8. Number of attempts for placing a peripheral intravenous catheter 
9. Postoperative nausea and vomiting (PONV) 
 
Safety Endpoints: 
10. Unplanned postoperative admission to an intermediate care unit (IMC) or intensive 
care unit (ICU) due to respiratory insufficiency. 
11. Confirmed Bronchopulmonary aspiration 
12. Death within observation period 

 
 
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3.5.3 Analysed population 
See inclusion and exclusion criteria. Analysis is per intention to treat. 
3.6 Participant Timeline and Individual Study Visits 
Follow-up per patient: Until completion of the last Visit (regularly 2 h ± 30 min after procedure, 
up to 48 h after procedure if e.g. bronchopulmonary aspiration is suspected.) 
Duration of intervention per patient: From randomisation until call to the operating room. 
 
Informed Consent, inclusion and withdrawal from the study is handled according to ICH-GCP. 
3.6.1 Visit 1: Enrolment in the Trial 
Screening, registration and Randomisation (- 28 days up to -0 days before surgery):  
Generally, the investigator or authorised qualified members of the study group in the trial site 
screen potential patients eligible for recruitment up to 28 days before surgery for general 
participation on the basis of pre-existing data (e.g., as available in medical records). 
Registered patients will be randomised electronically using REDCap after enrolment: Qualified 
medical staff will gain limited access to the system using a personal password. Information to 
identify a participant uniquely and to confirm eligibility must be entered before the system will 
assign the randomised treatment allocation. Randomization will be automated by computer-
assisted generation of random numbers, which will be transferred into a randomization 
decision and triggered web-based by qualified medical staff, so that allocation to the 
interventions is ensured (allocation concealment). 
On the day of the surgery the patients fluid intake prior to anaesthesia will be noted on a 
worksheet. The respective worksheet will be handed out at enrolment to avoid recall bias. 
However, if the patient loses the worksheet, a new one is given to him. To ensure outcome 
assessor blinding the worksheet will be sealed in an envelope after the call to the operation 
room and until follow up is concluded. 
3.6.2 Visit 2: Intervention 
The intervention is described in detail in chapter 3.2. 
3.6.3 Visit 3: Assessments prior to anaesthesia induction 
To ensure safety, 30 min must have passed since call to the operation room and anaesthesia 
induction. The patient must also state that they have not drunk since being called to the 
operating room. 
Anaesthesia induction in the sense of this protocol is defined as the beginning of the injection 
of the hypnotic for general anaesthesia and beginning of the injection of the local anaesthetic 
for local/regional anaesthesia. 
 
The primary efficacy outcome is measured immediately before anaesthesia induction 
of anaesthesia. Authorised medical staff use a modified Bauer satisfaction 
questionnaire to assess thirst. 
 
To assess secondary outcomes the questionnaire will include an item for headache. 
 
To assure the number of attempts for placing a peripheral intravenous catheter is 
documented correctly, each staff member involved in the anaesthesia of the patient is 
interviewed. 
 
Vital signs including heart rate and blood pressure will be collected from the routine 
data. The highest value 5 min prior to anaesthesia induction of anaesthesia will be 
documented. 

 
 
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 
The blood sample for glucose levels might be drawn immediately prior to anaesthesia 
induction or immediately after anaesthesia induction (Values assessed within 15 min 
prior and 15 min after anaesthesia induction will be accepted). 
3.6.4 Visit 4: Assessments immediately after anaesthesia induction 
 
If relevant bronchopulmonary aspiration is suspected, it needs to be confirmed by 
bronchoscopy or radiology imaging up to 48 h after anaesthesia procedure. In that 
case the patient will be monitored for an additional 48 h and the outcome will be 
documented in the eCRF and the AE/SAE section if applicable. The sponsor is to be 
informed of every instance of confirmed bronchopulmonary aspiration within 24 h 
even if the SAE criteria are not met. The risk/benefit consideration has to be 
revaluated. 
 
Vital signs including heart rate and blood pressure will be collected from the routine 
data. The lowest value 15 min after anaesthesia induction will be documented. 
 
If not already done, a blood sample for glucose levels is to be drawn. 
3.6.5 Visit 5: Assessments at follow up (2 h ± 30 min after procedure) 
Follow up takes place 2 h ± 30 min after the procedure. For general anaesthesia this is 2 h 
after extubation. For regional anaesthesia this is 2 h after skin suture. 
 
CAM-ICU is a well validated59-61 score that has been used in the awakening ward setting to 
detect immediate onset delirium62. As described in “CAM-ICU Training Manual and FAQ”, the 
CAM-ICU is not applicable if RASS63 is -4 oder -5. 
If CAM-ICU is negative, the Bauer satisfaction questionnaire will be obtained with all items 
and the item “Headache”. 
If CAM-ICU is positive or indeterminable, the Bauer satisfaction questionnaire is considered 
indeterminable. Sicker patients being missing from the data might skew the data (Attrition-
Bias). 
An indeterminable Bauer satisfaction questionnaire will therefore be repeated on POD1. 
PONV for up to 2 hours will be documented in the following dimensions: Vomiting, retching, 
nausea, and/or use of rescue medication. 
The safety endpoints and feasibility assessments will be considered present if they occurred 
before the end of the last Visit. 
3.6.6 Premature Termination of the Intervention Phase for Individual Patients 
The trial intervention phase may be terminated prematurely in case of:  
1. 
Eligibility criteria are not met. 
2. 
At the judgement of the investigator for any other reason of medical prudence. 
3. 
On request of the patient. 
In case of premature termination of intervention phase, it is necessary to document the reason 
of termination and the current condition of the patient. 
3.6.7 Plan for Further Treatment 
Patients will be treated as usual after the individual treatment period of the clinical trial. 

 
 
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4 METHODS: ASSIGNMENT OF INTERVENTIONS 
4.1 Allocation 
Sequence Generation: Patients will be randomly assigned to either control or experimental 
group with a 1:1 allocation per computer generated randomisation schedule using permuted 
blocks of random sizes. The block sizes will not be disclosed. 
Concealment Mechanism: Patients will be randomised using a web-based randomisation 
system (embedded in REDCap). Allocation concealment will be ensured. 
4.2 Blinding 
HYDRATE is a outcome assessor blinded trial, since the intervention is not blindable. The 
attending anaesthesist can be unblinded during the safety interview before anaesthesia 
induction. The endpoint assessment will be blinded. 
If the safety interview is conducted in a way that unblinds the attenting anaesthesist (e.g. 
asking the patient if fluids were consumed in the past 2 h) measures must be taken to avoid 
unblinding the staff responsible for assessing the outcomes (e.g. conducting the safety 
interview while the staff assessing the outcome is not present in the room). If unblinding occurs 
the remaining visits should be conducted by blinded staff whenever feasable. 
Unblinding of the staff conducting outcome assesment will be documented in the eCRF for visit 
4-6 respectivly. 
5 METHODS: DATA COLLECTION, MANAGEMENT, ANALYSIS 
5.1 Data collection Methods 
5.1.1 Case Report Form (CRF) 
Data will be entered into an eCRF designed in REDCap by the Investigator or an authorised 
member of the study team.  
5.2 Retention 
As follow up ends before hospital-discharge, we do not expect relevant issues with retention. 
5.3 Data Management  
The information entered into the eCRF is systematically checked for completeness, 
consistency and plausibility by rules implemented in the EDC Tool such that discrepancies can 
be dealt with at data entry. 
5.3.1 Archiving 
All relevant trial documentation (Trial Master File) and the electronically stored data will be 
stored for at least 15 years by the sponsor after the trial’s completion. At the trial sites, the 
investigators’ files, patient identification lists, signed written consent forms, electronic copies 
of all eCRFs and the patients’ files will be stored for at least 15 years after the trial’s completion. 
If local rules or other legal requirements require longer periods of archiving, then these are to 
be met especially for the local patient files. 

 
 
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5.4 Endpoints 
Endpoints are assessed as described in chapter 3.6.3-3.6.5 
The primary efficacy outcome is thirst on an ordinary scale from 1 to 3. 
With the assessment of this patient relevant endpoint prior to anaesthesia we keep the 
Statistical Description of the trial hypothesis. 
5.4.1 Statistical Hypotheses/Statistical Estimation Method 
H0: Clear fluid intake until call to the operating room is not associated with reduced thirst at 
anaesthesia induction compared to restriction of clear fluid intake within 2 hours prior to 
anaesthesia induction on the Bauer satsifaction questionnaire item #3. 
The primary endpoint will be analysed by chi-square test. 
5.5 Sample Size 
We plan randomising n=174 patients. n = 174 (55 per group +5% Dropout) 
The primary endpoint of this study is thirst immediately before anaesthesia induction. For this 
purpose, the Bauer Satisfaction Questionnaire is dichotomised - "yes (moderate or strong)" vs. 
"no thirst". The three groups will be compared with each other. In the control group, based on 
Bauer et al, 2001, a value of 53% is assumed64. Based on our own experience it is assumed 
that the experimental intervention (group 3) has a relative effect of 50% and therefore only 
26.5% of patients are still thirsty. For group 2 (Instructed guideline adherence) a somewhat 
weaker effect is assumed. We assume that thirst can be reduced to 30% in this group. 
In order to detect these differences between all three groups using a Chi² test with a power of 
80%, a total of 165 patients is needed - 55 patients per group. 
Drop-outs 
Assuming 5% drop-outs or non-informative patients we require 58 patients per group. 
5.6 Statistical Methods 
5.6.1 Analysis Population 
The Full Analysis Set (FAS) will be as close as possible to the ideal implied by the intention-
to-treat-principle. 
5.6.2 Planned Methods for Analysis 
Standard methods of descriptive statistics (e.g. chi-square test for the primary endpoint) will 
be used always indicating the number of valid and missing values. Summary statistic will be 
reasonably rounded to avoid pseudo-precision.  
 
Demographic and other baseline parameters will be described for the whole FAS and by 
randomisation arm using standard methods appropriate to the scale. 
 
Patients will be listed on whom no intervention or an intervention not corresponding to the 
randomisation arm was performed. 
6 METHODS: HARMS/ ADVERSE EVENTS (AE/SAE) 
The focus of this clinical trial is to find an appropriate fluid fasting strategy to optimize the risk-
benefit ratio. HYDRATE investigates different fasting strategies concerning patient thirst. 

 
 
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Immediate safety of drinking fluid is not in the primary focus of the trial and generally 
considered safe. 
Therefore, the collection, documentation and notification of safety relevant events are adapted 
for this clinical trial. Following data are of special interest:   
 
Data defined as end points (primary, secondary and safety). 
6.1 Definition of (serious) adverse events 
6.1.1 Adverse Events (AE)  
Adverse events encompass any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease that arise newly or worsen after the 
beginning of the intervention. 
6.1.2 Serious Adverse Events 
An adverse event is defined to be serious if it 
 results in death, 
 is life-threatening, 
 requires in-patient hospitalization or prolongation of existing hospitalization, 
 results in persistent or significant disability/incapacity 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused death had it 
been more severe.  
Medical and scientific judgement should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the patient 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should also usually be considered serious.  
6.2 Documentation of (serious) adverse events 
Within this trial all variables defined as safety outcomes meeting the definition of AE/SAE 
will have to be reported to the Investigator in writing as soon as possible and documented on 
the eCRF. The eCRF has to be filled in shortly after each study visit. 
6.3 Other Safety Relevant Issues 
Other safety issues also qualify for expedited reporting where they might substantially alter the 
current benefit-risk assessment of an investigational intervention or would be sufficient to 
consider changes in the investigational intervention or in the overall conduct of the trial, for 
instance: 
New events related to the conduct of a trial likely to affect the safety of subjects, such as:  
 
a serious adverse event which could be associated with the trial procedures, and 
which could modify the conduct of the trial, 
 
a significant hazard to the subject population such as lack of efficacy of 
intervention, 
 
a major safety finding from a newly completed preclinical study, 
 
a temporary halt of a trial for safety reasons if the trial is conducted with the same 
investigational intervention in another country by the same sponsor. 

 
 
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6.4 Therapeutic Procedures 
If a patient requires treatment as a result of an adverse event, then it must meet the recognised 
standards of medical care in order to restore the patient’s health. Appropriate resuscitation 
devices and medication must be available in order to treat the patient as quickly as possible in 
the event of an emergency. 
The actions taken to treat the AE/SAE must be documented by the investigator either in the 
appropriate CRF and/or using additional documents. 
6.5 Dealing with Pregnancy  
Pregnant and obstetric patients will not be enrolled in this trial. 
7 ETHICS AND DISSEMINATION 
7.1 GCP-Statement 
All persons participating in the conduct of the trial (sponsor, authorised representative of the 
sponsor, investigators, etc.) commit themselves to observe the Declaration of Helsinki (Version 
Fortaleza 2013), 66 as well as all pertinent national laws and the current International 
Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP). 
7.2  Initial Submission  
7.2.1 General considerations 
General ethical considerations also include the consideration and compliance with the 
following standards, laws and provisions: Declaration of Helsinki, 66 EU Commission directive 
2005/28/EC “Good clinical practice” (GCP), Proposal for Safeguarding Good Scientific 
Practice, and the EU Directive 95/46/EC (Data protection). 
7.2.2 Submission to the Ethics Committee and Federal Authority 
The protocol and all other associated documents will be submitted to the leading EC of the 
University Würzburg for appraisal. The trial can start only after obtaining a positive appraisal 
by the leading EC. All documentation regarding the submissions and their results must be filed 
in the Trial Master File (TMF). 
7.3 Protocol Amendments 
Changes made to the protocol that was appraised positively by the EC must be positively 
reappraised and approved if the changes 
- 
are such that they may affect the subjects' safety, e.g. fundamental changes to the 
therapeutic procedures, 
- 
result in further data collection that necessitates changes to the patient information 
and/or informed consent form, 
- 
affect the interpretation of the scientific documents upon which the trial is based or the 
significance of the results of the trial, 
- 
significantly affect the leadership or conduct of the trial. 
In order to ensure most comparable conditions during trial conduct and in the interest of valid 
statistical analyses, the investigators or any other person involved in the trial conduct may not 
alter the study conditions agreed upon and set out in this protocol. 

 
 
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Amendments should be made only in exceptional cases. Any amendment must be set out in 
writing, at the same time giving the reasons, and signed by all parties concerned. The 
amendment then becomes part of the study protocol and is to be filed in the TMF. 
Amendments which might have an impact on the well-being of the subject (major amendments) 
such as the use of additional invasive procedures require an additional approval by the EC. In 
addition, a further informed consent form is to be signed by all trial subjects enrolled in the trial 
who might be affected by the amendment. In case of substantial changes new approvals of 
the leading EC are required before the changes become effective. Minor changes will only be 
submitted to the EC in a written form. 
The investigator may implement a deviation from, or a change of the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior EC approval opinion. As soon as possible, 
the implemented deviation or change, the reason for it, and if appropriate, the proposed 
protocol amendment(s) should be submitted to the investigator for agreement. 
7.4 Data protection and Confidentiality 
Within this study, personal data from the trial subjects incl. data regarding the therapy and the 
course of disease (medical results) will be collected locally at the trial site.  
The data for the trial will be stored and processed in pseudonymised form (i.e. without 
reference to the patient’s name) with the aid of an identification number. The patient’s name 
will not appear on any case report form or in any other trial document submitted to the eCRF. 
All collected data will be kept confidential. 
Data access is limited to authorised persons. Measures are taken to prevent loss of data and 
that the laws pertaining to data protection are observed. The data are protected from third party 
access and only members of the trial are permitted to have access. These members are sworn 
to secrecy.  
In the event of withdrawal of consent, the necessity for storing data will be evaluated. Data not 
needed will be deleted immediately. Personal data will be stored in an anonymous manner 
after reaching the study aim/after finishing of all concomitant scientific projects 15 years at the 
latest, if there are no other regulatory or contractual time periods for archiving. 
7.4.1 Declaration regarding Data Protection 
During data entry, processing and analysis all requirements of the data protection act will be 
taken into account. Access to the data is strictly limited to authorised persons. Data are 
protected against unauthorised access. 
7.4.2 Declaration regarding the Pseudonymised Transfer of Personal Data  
The sponsor certifies herewith that the transfer of pseudonymised personal data will take place 
according to the documentation and communication regulations in §§ 12 und 13 of the GCP-
guidelines. 
7.4.3 Declaration regarding Data-Sharing 
The data on which the primary publication of the HYDRATE trial results was based will be 
shared with interested scientists on request (e.g. for meta-analyses, health related registers or 
other scientific questions) if the sponsor agrees. Shared data will be anonymized. This offer 
extends for at least five years. 

 
 
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8 ADMINISTRATIVE AGREEMENTS 
8.1  Adherence to the Protocol 
The clinical trial described here will be conducted and analysed in accordance with local laws 
(GCP-Verordnung) and ICH guidelines for Good Clinical Practice (GCP). 
Protocol violations are all deviations from the procedures outlined in this document.  
After a patient has been enrolled, it is the investigator's responsibility to avoid protocol violation 
in order to obtain unbiased data for the trial. Major protocol violations will be reported to the 
investigator/sponsor as soon as possible. All protocol violations will be documented and 
discussed with the responsible biometrician before closing the data base and carrying out the 
statistical analysis.  
The investigator must ensure that the recorded data are documented as per protocol. Minor 
variations are an inevitability but must be documented together with a justification. 
Protocol violations are documented in the eCRF. 
8.2  Funding and Insurance 
Patients are insured at Newline Europe Versicherung AG, Köln. 
 
The number of the insurance policy is: NEV084616A 
 
Copies of both insurance policies and the insurance conditions will be filed in the investigators 
file. A copy of insurance conditions will be handed over to the patient during informed consent 
process. 
8.3 Publication Policy and Registration 
The HYDRATE-Trial shall be published under the lead of the investigator together with 
contributing partners in a peer-reviewed journal, irrespective of the trial results. The publication 
policy will follow the recommendations of Good Scientific Practice (GSP) of the Deutsche 
Forschungsgemeinschaft (DFG, http://www.dfg.de) and will meet the criteria of the 
International Committee of Medical Journal Editors (http://www.icmje.org). 
 
Prior to study start, the clinical trial will be registered in a public trial registry (ClinicalTrials.gov). 
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amendment by the 48th General Assembly, Somerset West (Rep. of South Africa) 1996. 
10 APPENDIX 
10.1 Classification of Adverse Events 
10.1.1 Degree of seriousness 
The degree of seriousness of an Adverse Events will be determined in accordance with the 
definitions in 7.3.1 and 7.3.2..  
10.1.2 Assessment of Intensity  
The assessment of the intensity accords with CTCAE V4.065 

 
 
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Mild Adverse 
Event 
 
asymptomatic or mild symptoms;  
 
clinical or diagnostic observations only;  
 
intervention not indicated. 
Moderate 
Adverse Event 
 
minimal, local or non-invasive intervention indicated;  
 
limiting age-appropriate instrumental ADL*1. 
Severe Adverse 
Event 
 
medically significant but not immediately life-threatening;  
 
hospitalization or prolongation of hospitalization indicated; 
 
disabling; 
 
limiting self care ADL** 
Life-threatening 
Adverse Event 
 
Life-threatening consequences; 
 
urgent intervention indicated  
Death related to 
Adverse Event 
 
10.1.3 Determining the Causal Relationship  
The investigator/the deputy or the authorised medical staff must assess whether or not the 
Adverse Event is causally related to the intervention. The following classification is to be used.  
 
Reasonable possibility 
 
No reasonable possibility 
10.1.4 Expected/Unexpected 
Adverse Events are unexpected if they are no safety outcomes or regurgitation. 
10.1.5 Outcome of an Adverse Event 
The outcome of an Adverse Event is classified as follows: 
 
recovered/resolved 
 
recovering/resolving 
 
not recovered/not resolved 
 
recovered/resolved with sequelae 
 
fatal* 
 
unknown  
*Note: A patient’s death is not in itself an event, but the consequence of one. The event that 
led to the patient’s death must be documented completely. 
 
 
                                               
1 Activities of Daily Living (ADL):  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 

 
 
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11 PROTOCOL SIGNATURES AND AGREEMENT 
 
Confirmation of the Final Protocol 
We hereby certify that this is the final version of the protocol: 
 
Investigator: 
Dr. Tobias Eberhard Haas 
24.06.2024 
Date 
 
Signature 
Biometrician: 
Prof. Dr. Peter U. Heuschmann 
 
Date 
 
Signature 
 
Protocol Agreement 
Herewith I declare that I have read and understood the present protocol and agree to honour 
each part of it. I will ensure that all the patients enrolled in the trial by my site will be treated, 
observed and documented in accordance with this protocol. I will ensure that all persons 
assisting with the study under my supervision are adequately informed about the protocol, the 
investigational product and their duties.  
 
Date: 
_________________________ 
 
 
Signature of Investigator: 
_________________________ 
 
 
Affiliation/address (stamp):  
_________________________ 
 
_________________________ 
 
_________________________ 
 
_________________________