Early Initiated Vasopressor Therapy vs. Standard Care of Primarily Fluid Therapy in Hypotensive Patients in the Emergency Department - A Pragmatic, Multi-center, Superiority, Randomized Controlled Trial
Phase: PHASE3
Conditions: Shock, Shock, Septic, Hypotension, Hypotension and Shock, Hypotension Symptomatic, Hypovolemia, Hypovolemic Shock, Hypovolemic
Sponsor: Odense University Hospital

 
 
Early initiated vasopressor therapy vs. standard care of primarily fluid 
therapy in hypotensive patients in the emergency department – A 
pragmatic, multi-center, superiority, randomized controlled trial 
Acronym: VASOSHOCK 
 
 
 
 
 
 
TRIAL PROTOCOL 
Version 2.1 
 09-12-2024 
 
EU CT ID: 2023-504584-16-00 
Clinicaltrials.gov ID: NCT05931601 
Coordinating Investigator 
Lasse Paludan Bentsen, M.D. 
Registrar and PhD-fellow in Emergency Medicine 
 
Sponsor-Investigator 
Mikkel Brabrand, M.D., PhD 
Clinical Professor and Senior Consultant in Emergency Medicine 
Research Unit for Emergency Medicine 
Department of Emergency Medicine 
Odense University Hospital 
Kløvervænget 25c, DK-5000 Odense C, Denmark 

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Table of Contents 
2 
Preface ............................................................................................................................................................... 8 
Sponsor statement .............................................................................................................................................. 9 
Overview ......................................................................................................................................................... 10 
Trial flow chart ................................................................................................................................................ 13 
Steering committee .......................................................................................................................................... 14 
Trial sites and investigators ............................................................................................................................. 15 
List of abbreviations ........................................................................................................................................ 16 
Modifications and amendments ....................................................................................................................... 18 
1. Background ................................................................................................................................................. 23 
1.1. Shock and hypotension in emergency departments ............................................................................. 23 
1.2. Evaluation of fluid therapy responsiveness in shock ........................................................................... 23 
1.3. Excessive fluid therapy and current practice in Scandinavian EDs ..................................................... 24 
1.4. Early vasopressor therapy for hypotension and shock ......................................................................... 25 
1.5. Hyperlactatemia and lactate clearance in shock ................................................................................... 27 
1.6. Biochemical, neuroendocrinal, hormonal and acid-base changes in critical illness ............................ 28 
1.7. Rationale for studying early initiated peripheral noradrenaline in the Scandinavian setting ............... 29 
1.8. Systematic review of existing literature ............................................................................................... 29 
1.9. Choice of comparators with prior and on-going studies on early vasopressor therapy ........................ 30 
Table 1: Overview of VASOSHOCK, ARISE and EVIS ............................................................................... 32 
2. Trial objectives and hypotheses ................................................................................................................... 34 
2.1. Aim ....................................................................................................................................................... 34 
3. Trial Design ................................................................................................................................................. 35 
3.1. Overview .............................................................................................................................................. 35 
3.2. Allocation and randomization .............................................................................................................. 35 
3.3. Interventions ......................................................................................................................................... 35 
3.3.1. Termination of intervention .......................................................................................................... 36 

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3.3.2. Weaning of noradrenaline infusion during ED admittance .......................................................... 37 
3.3.3. Treatment during 24-hour intervention in other departments ....................................................... 37 
3.3.4. Early termination of intervention .................................................................................................. 38 
3.4. Control group ....................................................................................................................................... 38 
3.5. Blinding ................................................................................................................................................ 38 
3.6. Sub-studies ........................................................................................................................................... 38 
3.6.1. Sub-study 1: Long term follow-up ................................................................................................ 39 
3.6.2. Sub-study 2: Non-invasive hemodynamic monitoring of patients with hypotension and shock .. 39 
3.6.3. Sub-study 3: Lactate normalization in hypotensive shock patients .............................................. 39 
3.6.4. Sub-study 4: Biochemical, neuroendocrinal, hormonal and acid-base changes in shock and 
hypotension ............................................................................................................................................. 40 
3.6.5. Sub-study 5: Thermography changes in early treatment of hypotension and shock ..................... 41 
4. Setting and patient population ..................................................................................................................... 42 
4.1. Setting .................................................................................................................................................. 42 
4.2. Eligibility criteria ................................................................................................................................. 42 
4.3. Inclusion criteria ................................................................................................................................... 42 
4.4. Exclusion criteria ................................................................................................................................. 43 
4.5. Co-enrolment........................................................................................................................................ 43 
5. Outcomes ..................................................................................................................................................... 44 
5.1. Primary outcome .................................................................................................................................. 44 
5.2. Secondary outcomes ............................................................................................................................. 44 
5.3. Tertiary and exploratory outcomes ...................................................................................................... 44 
5.4. Safety outcomes ................................................................................................................................... 45 
6. Pharmacovigilance ...................................................................................................................................... 46 
6.1. Choice of IMP ...................................................................................................................................... 46 
6.2. Dosing regime and rationale for dosing levels ..................................................................................... 46 
6.3. Storage and handling of the IMP.......................................................................................................... 47 
6.3.1. Infusion pumps ............................................................................................................................. 48 

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6.4. Preparation of the IMP ......................................................................................................................... 48 
6.4.1. Table 2: Noradrenaline mixing dose ............................................................................................. 49 
6.5. Termination and destruction of the IMP .............................................................................................. 50 
6.6. Choice of infusion route ....................................................................................................................... 50 
6.7. Insertion of peripheral catheters ........................................................................................................... 51 
6.8. Suspected extravasation ....................................................................................................................... 51 
6.9. Unintended overdose of noradrenaline ................................................................................................ 52 
7. Safety and harm ........................................................................................................................................... 53 
7.1. Definitions ............................................................................................................................................ 53 
7.2. General considerations and risk proportionate approach ..................................................................... 53 
7.3. Assessed adverse events and reactions ................................................................................................. 55 
7.3.1. Noradrenaline extravasation ......................................................................................................... 55 
7.3.2. Suspected or evident overdose of noradrenaline .......................................................................... 55 
7.4. Suspected Unexpected Serious Adverse Events (SUSAR) .................................................................. 56 
7.4.1. Fluid treatment .............................................................................................................................. 56 
7.5. Follow-up period for adverse events and reactions .............................................................................. 56 
7.6. Registration .......................................................................................................................................... 56 
7.7. Reporting .............................................................................................................................................. 57 
8. Sample size and statistical analysis plan ..................................................................................................... 58 
8.1. Sample size calculation ........................................................................................................................ 58 
8.2. Statistical analysis plan ........................................................................................................................ 58 
8.2.1. General considerations .................................................................................................................. 58 
8.2.2. Missing data .................................................................................................................................. 59 
9. Data collection and management ................................................................................................................. 60 
9.1. Data collection methods ....................................................................................................................... 60 
9.1.1. HemoSphere™ data ...................................................................................................................... 60 
9.2. Participant retention and ensuring complete follow-up ....................................................................... 60 
9.2.1. Replacement of data from participants no longer enrolled in the trial .......................................... 61 

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9.2.2. Replacement of participants withdrawn during the trial ............................................................... 61 
9.3. Data management ................................................................................................................................. 61 
9.3.1. Data access .................................................................................................................................... 62 
9.4. Data to be collected .............................................................................................................................. 63 
9.4.1. Data collected bedside on the paper-CRF ..................................................................................... 63 
9.4.2. Data collected from the registered safety reporting or electronic patient records ........................ 63 
9.4.3. Data extracted from the medical records and bedside, including from patient monitors for either 
identification log, papir-CRF, data entry directly in the eCRF or storage in the secure SharePoint site. 63 
9.4.4. Data collected in the screening log ............................................................................................... 64 
9.4.5. Data collected from the HemoSphere™ monitor ......................................................................... 65 
9.4.6. Data collected from blood or urine samples ................................................................................. 65 
9.5. Reporting of the summary of results .................................................................................................... 65 
10. Ethical considerations ................................................................................................................................ 66 
10.1. Research in shock and hypotension ................................................................................................... 66 
10.1.1. General considerations ................................................................................................................ 66 
10.1.2. Research Biobank ....................................................................................................................... 68 
10.1.3. Collection of venous or arterial blood samples ........................................................................... 68 
10.1.4. Urine samples for mRNA analysis ............................................................................................. 69 
10.1.5. Non-invasive hemodynamic monitoring of patients with hypotension and shock ..................... 69 
10.1.6. Thermography changes in early treatment of hypotension and shock ........................................ 69 
 N ................................................................................................................................................................. 70 
10.2. ational regulations .............................................................................................................................. 70 
10.3. Low intervention trial ......................................................................................................................... 70 
10.4. Informed consent procedures ............................................................................................................. 71 
10.4.1. Ethical review committee ........................................................................................................... 71 
10.4.2. Trial-specific procedures ............................................................................................................ 71 
10.4.3. Screening and enrolment ............................................................................................................ 72 
10.4.4. Consent for participation ............................................................................................................ 72 

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10.4.5. Danish procedures ....................................................................................................................... 73 
10.4.6. Swedish procedures .................................................................................................................... 75 
10.4.7. Registration of obtained consent for participation ...................................................................... 78 
10.4.8. Participation in sub-studies ......................................................................................................... 78 
10.5. Protection of patient data ................................................................................................................... 78 
10.5.1. Overall procedures ...................................................................................................................... 79 
10.5.2. Specific swedish procedures ....................................................................................................... 79 
10.5.3. Measures in case of breach of data security ................................................................................ 79 
10.5.4. Insurance ..................................................................................................................................... 80 
10.5.5. End of trial .................................................................................................................................. 80 
11. Monitoring ................................................................................................................................................. 81 
11.1. Good Clinical Practice ....................................................................................................................... 81 
11.2. Independent Data Monitoring Committee (IDMC) ............................................................................ 81 
11.3. Auditing ............................................................................................................................................. 81 
12. Timeline ..................................................................................................................................................... 82 
12.1.1. Biobank Timeline ....................................................................................................................... 85 
13. Feasibility .................................................................................................................................................. 86 
14. Publication and dissemination ................................................................................................................... 88 
14.1. Authorship .......................................................................................................................................... 88 
15. Data sharing ............................................................................................................................................... 89 
16. Funding ...................................................................................................................................................... 90 
17. Tasks and responsibilities .......................................................................................................................... 91 
17.1. Sponsor-Investigator and Coordinating Investigator ......................................................................... 91 
17.2. National Coordinating Investigator in Sweden .................................................................................. 91 
17.3. Steering committee ............................................................................................................................. 91 
17.4. Project coordinator ............................................................................................................................. 91 
17.5. Principal Investigators at each trial site .............................................................................................. 92 
17.6. Research staff ..................................................................................................................................... 92 

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17.7. Clinical team ...................................................................................................................................... 92 
17.8. Good clinical practice unit: ................................................................................................................ 92 
18. References ................................................................................................................................................. 93 
19. Appendices .............................................................................................................................................. 106 
Appendix 1: CONSORT diagram draft ......................................................................................................... 106 
Appendix 2: Clinical Frailty Scale (Danish) ................................................................................................. 107 
Appendix 3: Conflict of interests for steering committee ............................................................................. 108 
Appendix 5: Summary of product characteristic for noradrenaline .............................................................. 109 
Appendix 6: Long-term follow up study ....................................................................................................... 122 
 
 
 

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Preface 
We hereby declare, as Sponsor-Investigator and Coordinating Investigator, that the trial “Early 
initiated vasopressor therapy vs. standard care of primarily fluid therapy in hypotensive patients in 
the emergency department – A pragmatic, multi-center, superiority, randomized controlled trial 
(VASOSHOCK)” will be conducted in accordance with the written protocol. The trial will follow 
the applicable national and international laws, guidelines including the European Regulations,1 
ICH-GCP 2 and the revised version of the Declaration of Helsinki on ethical principles for medical 
research involving human subjects.3  
This protocol is developed in accordance with the Standard Protocol Items: Recommendations for 
International Trials (SPIRIT) statement.4 
This protocol was written by the Coordinating Investigator with input and revision suggestions by 
the Steering Committee. The Sponsor-Investigator and Coordinating Investigator takes 
responsibility that any substantial changes or modifications will be documented and reported to all 
relevant parties when applicable.  
 
Coordinating Investigator – Department of Emergency Medicine – Odense University 
Hospital 
 
 
 
_____________________________________________________________ 
Lasse Paludan Bentsen, M.D. 
 
 
Date 
 
 
Sponsor and Principal Investigator – Department of Emergency Medicine – Odense 
University Hospital 
 
 
 
_____________________________________________________________ 
Mikkel Brabrand, M.D., Ph.d. 
  
 
Date 

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Sponsor statement 
As Sponsor, I hereby confirm that all investigators, their related trial institutions, and departments 
have agreed to be involved in the clinical trial and agree to allow trial related monitoring, audit and 
inspection from the relevant authorities, including direct access to source data and documents.  
 
Sponsor and Principal Investigator 
Department of Emergency Medicine  
Odense University Hospital 
 
 
 
 
 
_____________________________________________________________ 
Mikkel Brabrand, M.D., Ph.d. 
  
 
Date 
 
 
 

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Overview 
 
 
Protocol version 
Version 2.1 
Trial registrations 
EU CT ID: 2023-504584-16-00 
Clinicaltrials.gov ID: NCT05931601 
Date of registration 
13-06-2023 
Start of trial 
08-12-2023 
Planned end of trial 
31-08-2026 
Planned biobank termination 
31-08-2031 
Funding 
The PhD Fund of the Region of Southern Denmark, The 
Medicine Fund of the Danish Regions and The Region of 
Southern Denmark and Region Zealand Research Fund. 
Sponsor and Principal Investigator 
Mikkel Brabrand 
Sponsor-Investigator 
Clinical Professor and Senior Consultant 
Department of Emergency Medicine 
Odense University Hospital 
mikkel.brabrand@rsyd.dk   
Contact 
Lasse Paludan Bentsen 
Coordinating Investigator 
Registrar and PhD-Fellow 
Department of Emergency Medicine 
Odense University Hospital 
lasse.paludan.bentsen@rsyd.dk  
Country of recruitment 
Denmark 
Studied subject 
Hypotension and shock not related to anaphylaxis, cardiogenic, 
neurogenic, or haemorrhagic cause. 
Intervention 
Early initiated peripherally infused noradrenaline during ED 
admittance 
Comparator 
Standard treatment according to local guidelines without ED 
initiation of vasopressor therapy 
Inclusion criteria 
1. At least 18 years of age  
2. Signs or suspicion of hypotension or shock (of any 

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type such as septic, vasodilatory or hypovolemic not 
included in the exclusion criteria) defined as: 
a. SBP < 100mmHg or MAP < 65 mmHg combined 
with lactate > 2.0 mmol/L, 
b. Physician defined blood pressure for the 
individual patient combined with a lactate > 2.0 
mmol/L 
c. Either SBP < 100mmHg or MAP < 65mmHg 
with obvious signs of shock with any lactate level 
evaluated by either two non-specialist physicians 
(e.g. registrar medical doctors) or one specialist 
physician.  
3. Received at least 500ml of intravenous fluid before 
study inclusion (Including prehospital administration) 
4. Clinical Frailty Score (CFS) of ≤4. If CFS is ≥5 and the 
treating physician find the patient suitable for ICU 
admittance, the participant can be enrolled, if the on-call 
ICU doctor would accept the patient for ICU admittance. If 
the treating physician is unsure of ICU eligibility, 
regardless of CFS score, the patient should be consulted 
with the ICU consultant before study inclusion.  
Exclusion criteria 
1. Cardiogenic, anaphylactic, haemorrhagic, or neurogenic 
shock suspected by the treating physician.  
2. Fertile women (<60 years of age) with positive urine 
human gonadotropin (hCG) or plasma-hCG or women 
breastfeeding. 
3. Patient deemed terminally ill or with a severe co-morbid 
status resulting in non-eligibility for ICU admittance 
decided by either the treating physician or ICU consultant. 
4. Severe organ failure outside circulatory failure that 
requires immediate ICU admission.  

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5. Known allergy to noradrenaline. 
6. Previously enrolled in the trial  
Study type 
Interventional study  
Allocation: Block Randomized (1:1)  
Intervention model: Parallel group  
Blinding: None 
Target sample size 
320 
Recruitment status 
Recruiting 
Primary outcome 
Proportion of patients achieving either SBP >100 mmHg or 
MAP > 65 mmHg or a target blood pressure set by the treating 
physician at 90 (±15) minutes after inclusion 
Key secondary outcomes 
Number of ICU free days alive within 30 days 
Time without shock within 24 hours 
30-day all-cause mortality.  
In-hospital all-cause mortality 
 
 

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Trial flow chart 
 

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Steering committee 
Lasse Paludan Bentsen, M.D. 
Coordinating Investigator 
Emergency Medicine Registrar and Ph.D. 
fellow 
 
Research Unit for Emergency Medicine 
Department of Emergency Medicine 
Odense University Hospital 
 
Department of Emergency Medicine 
Lillebaelt University Hospital, Kolding 
 
Mikkel Brabrand, M.D., Ph.D.  
Sponsor and Principal Investigator  
Professor and Senior Consultant  
 
Research Unit for Emergency Medicine  
Department of Emergency Medicine  
Odense University Hospital  
 
Thomas Strøm, M.D., Ph.D.  
Professor and Senior Consultant  
 
Department of Anesthesiology and Intensive 
Care Medicine  
Hospital of Southern Jutland 
  
Department of Anesthesiology and Intensive 
Care Medicine  
Odense University Hospital  
 
 
Peter Biesenbach, M.D.  
Consultant and Site Principal Investigator  
 
Department of Emergency Medicine University 
Hospital of Southern Denmark Esbjerg  
 
Jens Henning Rasmussen, M.D.  
Head of Department, Consultant and Site 
Principal Investigator  
 
The Emergency Department  
Bispebjerg Hospital  
 
 
Gerhard Tiwald, M.D.  
Head of Department, Consultant and Site 
Principal Investigator  
 
The Emergency Department  
Zealand University Hospital, Køge  
 
Nikolaj Raaber 
Senior Consultant and Site Principal 
Investigator 
 
The Emergency Department 
Aarhus University Hospital 
 
 
Jakob Lundager-Forberg 
Senior Consultant and Site Principal 
Investigator 
 
Akutsjukvård 
Skånes Sjukhus Nordväst - Helsinborg 
 
 

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Trial sites and investigators 
All trial sites and principal investigators are listed in the Clinical Trials Information System (CTIS) 
listing.  
 
 
 
 

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List of abbreviations 
AE: Adverse Event 
APTT: Activated Partial Thromboplastin Time 
AR: Adverse Reaction 
CFS: Clinical Frailty Score 
CI: Cardiac Index 
 
CO: Cardiac Output 
CRF: Case Report Form 
CTIS: Clinical Trial Information System 
CVC: Central Venous Catheter 
DBP: Diastolic Blood Pressure 
DIC: Disseminated Intravascular Coagulopathy 
DMP: Data Management Plan 
ECG: Electrocardiogram 
ED: Emergency Department 
EoT: End of Trial 
GCP: Good Clinical Practice 
GDPR: General Data Protection Regulation 
ICH-GCP: International Conference on Harmonisation of Good Clinical Practice 
ICMJE: International Committee of Medical Journal Editors 
ICU: Intensive Care Unit 
IMP: Investigational Medicinal Product 
INR: International Normalized Ratio 
MAP: Mean Arterial Pressure 
NIBP: Non-invasive Blood Pressure 
OUH: Odense University Hospital 
PVC: Peripheral Venous Catheter 
RSI: Reference Safety Information 
SAP: Statistical Analysis Plan 
SBP: Systolic Blood Pressure 
SAE: Serious Adverse Event 
SAR: Serious Adverse Reaction 

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SCC: Surviving Sepsis Campaign 
SD: Standard Deviation 
SmPC: Summary of Product Characteristics 
SOP: Standard Operating Procedure 
SpO2: Peripheral Saturation of O2 
SUSAR: Suspected Unexpected Serious Adverse Event 
SV: Stroke Volume 
SVR: Systemic Vascular Resistance 
TMF: Trial Master File 
 
 
 
 
 
 
 
 
 
 

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Modifications and amendments 
13-06-2023: Version 1.0 
25-08-2024: Version 1.1 
• Removed the list of trial sites and principal investigators and added information where to 
locate these. 
• Product summary changed to summary of product characteristics to follow correct 
nomenclature. 
• Changed LPB to Coordinating Investigator and MB to Sponsor and Principal Investigator at 
OUH.  
• Updated the inclusion criteria point 2 regarding types of shock included in the trial.  
• Updated section 3.7 to not include data from national registers. Subsequently to this, section 
9.4 and appendix 6 has also been updated. 
• Added section 3.9 criteria for early trial termination and moved trial flow-chart to section 
3.10.  
• Updated the rationale of the dosing regimen for the IMP, section 6.2. 
• Updated section 6.4 regarding mixing of the IMP including tables for dosages mixed with 
either isotonic saline or glucose and specified documentation of the IMP.  
• Updated section 7.0 and subsections for evaluating AE and SAE including reporting 
procedures. Subsequently, appendix 4 including the attached flow-chart has also been 
updated.  
• Update to section 9.2.1 regarding data from deceased participants.  
• Updated section 9.3 on data protection regulations.  
• Added section 9.5 on reporting of the summary of results.  
• Updated section 10.0 and subsections regarding screening procedures, ethical requirements, 
identification of the next of kin/legal representative, legal guardian, how consent obtained in 
case of the deceased participant and data protection rules.  
 
15-03-2024: Version 1.2 
• Updated the primary outcome for a more feasible time frame without altering the aim 
• Updated secondary outcomes to me more specific 
• Updated the inclusion criteria for shock 

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• Updated the start of trial in the overview 
• Updated the background section 
• Updated the table for the mixing dose of noradrenaline removing formatting errors 
• Added description of sub-studies and updated the background, data collection and 
management and ethics section accordingly.  
• Updated the funding section 
• Updated appendix 2 (Clinical Frailty Scale) to the Danish version. 
• Added the clinicaltrials.gov identifier 
• Updated the Steering Committee to include Gerhard Tiwald, who was previously missing by 
formatting error 
• Changed PI in Gødstrup from Larshan Perinpam to Malik Kalmriz. 
• Added Bispebjerg Hospital with Jens Henning Rasmussen as Site PI. 
• Updated the list of abbreviations, the trial-flow chart and the timeline 
• Updated the authorship section 
• Updated the intervention section in relation to intervention period to account for local 
organisation differences between sites’ 
11-11-2024: Version 2.0 
• The protocol is revised with reorganization of several parts of the protocol to applicable 
sections following a more standard approach and clearing up certain sections that was 
previously placed incorrectly. Sections which was only moved are not part of the tracked 
changes. Sections revised, also after relocation, are tracked.  
• Minor updates on grammar throughout the document. 
• Internal bookmarks and cross-links is updated throughout the document. 
• The document has been revised throughout to describe current Scandinavian practices 
instead of Danish only. 
• Trial sites now refer to the CTIS registration.  
• Section 1, background, added a section about mRNA analysis is to describe a new sub-study 
addition. 
• Section 3, trial design, is updated with changes to the intervention procedures as current 
local practices might provide the opportunity for more secure line insertion and usage (such 
as midline) or better monitoring (such as arterial lines). 

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o Termination of treatment has been updated to be more precise. 
o Added a subsection for mRNA from plasma and urine samples as part of the biobank 
sub-study. 
• Section 4, setting and patient population, has new exclusion criteria added to ensure more 
clarity on which patients not being enrolled in the trial. Also, the inclusion criteria on fluid 
therapy has had the time restriction removed.  
• Section 5, outcomes, revised with removal of lactate at inclusion as outcome (it’s baseline 
data) and revision of currently planned outcomes. Specified which outcomes are considered 
safety outcomes.  
• Section 6, pharmacovigilance, is updated to provide a more pragmatic approach that 
considers the different local practices in medication handling, while still ensuring the same 
level of patient safety as previously mandated.  
• Section 6.6., added section on choice of infusion route, allowing other routes than peripheral 
if used in accordance with current local site practices. The previous approach to peripheral 
lines and safety are unchanged.  
• Section 7, safety and harm, is extensively revised to implement a risk proportionate 
approach as part of the low-intervention trial.  
• Section 9, data management, updated to be more clear and concise on how data is handled, 
including storage of consent forms to conform with different national regulations. Also, data 
collected has been revised to be more concise.  
• Section 10, ethical considerations, is thoroughly updated to emphasize the planned addition 
of a new member state concerned. The section is now divided into a Danish and Swedish 
section that describes the procedures for consent for each country. The Danish procedures, 
even after the update, is unchanged.  
• Section 11, monitoring, is updated for the Swedish GCP monitoring.  
• Section 14, authorship, is revised for the co-author criteria.  
• Section 17, tasks and responsibilities, is updated with description of a national coordinator 
in Sweden.  
 
09-12-2024: Version 2.1 
• Section 6.4 has been updated to clarify the timing of IMP mixing prior to administration and 
how batch numbers will be available for full traceability. 

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• Retracted the change of exclusion criteria 2.  
• Section 7.2 added a statement for SAE reporting and how this is handled by the 
investigators and Sponsor. 
• Section 7.7 added statement for description of safety reporting in the annual safety report.    
 
 

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1. Background 
1.1. Shock and hypotension in emergency departments 
Early recognition and treatment of shock is vital. Shock is widely defined as inadequate tissue 
perfusion, cellular damage and metabolic changes, which can lead to death.5 Shock is a common 
occurrence in the (ED).6 Over the course of 3 years, Odense University Hospital (OUH) had 
175,278 patient contacts and 2,137 (1.2%) presented with hypotension7 and data suggests that the 
number is increasing.8 At the same time, hypotension in the ED is associated with in-hospital 
mortality of 12% and even higher (33-52%) if identified in the pre-hospital setting.9 Fluid 
resuscitation in the ED and ICU for treatment of hypotension and improvement of organ perfusion 
is widespread 10,11 and amount of fluid infusion can vary greatly among patients.12.   
 
1.2. Evaluation of fluid therapy responsiveness in shock 
Shock identification can be complex and requires several parameters including abnormal vital signs, 
clinical evaluation and laboratory values including interpretation of acid-base disturbances.13-34 If a 
condition of shock is not evident, there is a risk of missing it and thereby fail to provide the 
appropriate treatment. Even though abnormal vital signs can accurately predict critical illness and 
mortality, they are unspecific for shock and can miss the condition in the early stages.27,31,35-38 
Evaluation of fluid responsiveness in a clinical setting can be complicated.39,40 This usually leads to 
bed-side clinical judgement, that can be difficult to interpret, as patients can present with a range of 
symptoms and parameters. Bed-side evaluation can include clinical presentation with skin turgor, 
assessment of cognitive status, measurement of blood pressure, pulse, capillary refill time and 
ultrasound (e.g. measurement of the inferior vena cava diameter and collapsibility).41 When 
evaluating fluid responsiveness in patients through invasive or non-invasive measurements, the 
therapeutic effects are best seen as change in Cardiac Index (CI), even though targets, such as 
increase in MAP, are frequently used due of the availability of this parameter.42-44 Other than MAP, 
these measurements are not universally available in the Scandinavian ED setting. However, the 
hemodynamic effect of fluid infusion can be short-lived. Previous studies have shown that any 
increase in blood pressure from fluid administration has vanished within one hour.45.  
In Scandinavian EDs, the most common current practice of hemodynamic monitoring is limited to 
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However, this method is close to, but not as precise as, invasive methods and risk of overestimating 
blood pressure during hypotensive events.46-49 Advanced hemodynamic measuring using invasive 
techniques like the pulmonary artery catheter and arterial cannulation is recommended for the 
monitoring of critically ill patients,50 but is not always available in the ED due to local guidelines.   
Newer equipment has been developed that can perform advanced hemodynamic measurements non-
invasively, potentially providing clinicians with a more precise understanding of the patients’ 
hemodynamic status without the need for invasive procedures.51 In addition, these methods provide 
continuous monitoring of parameters including blood pressure and therefore provides direct data of 
current hemodynamic measurements when compared to current intermittent methods.14 This 
equipment presents an opportunity for improved patient monitoring with far fewer complications 
than invasive measurements; however, the knowledge of the implications has only been sparsely 
studied in the ED setting.52 
Thermography is another tool which has shown possible prognostication of mortality in patients 
including correlation to systematic vascular resistance, stroke volume and other parameters. 
However, thermography has not yet been investigated specifically in the setting of shock and for 
evaluating treatment response.53-55 
 
1.3. Excessive fluid therapy and current practice in Scandinavian EDs 
Liberal fluid resuscitation, such as more than 5 litres over a short period of time, may cause harm56-
59 and hypotension that is not responsive to fluid therapy require earlier infusion of vasopressors 
such as noradrenaline60. Previous studies evaluating a restrictive approach to fluid therapy, such as 
less than 2-3 litres, seems feasible in both the ED for septic patients and the ICU for septic 
shock.61,62  Most studies on fluid resuscitation have been on patients admitted to intensive care 
(ICU), and thus only a subgroup of patients seen in the ED.63 The most recent study in restrictive 
use of fluid in septic shock, CLOVERS, did not show a benefit in this subgroup in regards to a more 
restrictive fluid approach compared to a more liberal approach.64 Canadian and international 
Surviving Sepsis guidelines recommend routine use of noradrenaline in hypotensive septic patients 
not responding to early fluid boluses, though the data for early treatment has previously been 
sparse60,65, at least until the CLOVERS study was published.64  
Current treatment of hypotensive patients in the ED varies by department, which could be due to the 
different organizational models in Denmark and Scandinavia.11,12,66,67 Emergency Medicine as a 

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specialty was founded in Denmark 2017, though the current organization of EDs was begun in 
2007. Therefore, till now and for the most part, EDs in Denmark are still staffed mostly by 
registrars, senior registrars, and consultants from other specialties than emergency medicine. Few 
Danish EDs are staffed 24/7/365 by at least one specialist in Emergency Medicine.66 For the rest of 
Scandinavia, the implementation of Emergency Medicine as a specialty ranges back to 2006 in 
Sweden but is not currently a fully-fledged specialty in Norway.68,69 
There are currently no national guidelines in Scandinavia, for treatment of undifferentiated shock. 
Current guidelines are usually focused on specific conditions, such as sepsis and septic shock, or 
adhere to the SSC recommendation.60 Others are written as local guidelines directed at a specific 
subgroups, such as patients already admitted to the ICU.  
In Scandinavia, the use of vasopressor treatment is not standard care in the ED, and they are 
primarily used in the perioperative or intensive care setting and administered by anaesthesiologists.6 
If vasopressor support is needed, the ED staff will contact the ICU consultant for admittance to the 
ICU and most vasopressor initiations are initiated after the patient have been transferred to the ICU. 
Only a few patients, to our knowledge, receive vasopressor therapy in the ED.70,71 Admittance to the 
ICU is usually by decision of the ICU consultant and most patients with medical conditions 
admitted to the ICU, are without severe restrictions in daily activities. Patients with moderate to 
severe restrictions might be deemed ineligible for admittance.72  
For many patients with hypotension from a non-bleeding cause, this results in use of fluid therapy 
to treat dehydration, intravascular depletion, hypotension or initial stages of shock.11,12,62 This 
approach might not stabilize the patient, due to only temporarily blood pressure increase, even 
though that’s the goal of the treatment, with risk of excessive fluid therapy and by that, possible 
complications. 11,12,58,62,63,73-77 Choice of fluid can differ by department, though normal saline and 
balanced crystalloids such as Ringers Acetate or Lactate, are the most commonly used.12,78 Previous 
international studies have shown that low-dose vasopressor therapy safely can be administered in 
the ED, and that this probably is sufficient care for most patients with circulatory mono-organ 
failure.60,74,79,80  
 
1.4. Early vasopressor therapy for hypotension and shock 
Vasopressors are commonly used for treatment of hypotension and shock.  One of these, 
noradrenaline, is a catecholamine, a natural hormone and neurotransmitter in the human body. 

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Noradrenaline has several acting sites in the human physiology, some of them consisting of blood 
pressure regulation, and subsequently organ and tissue perfusion, with primary action on α-
receptors in the blood vessels and partly β-receptors in the heart muscle.81 Noradrenaline, as well as 
other vasopressor and inopressors, have historically been indicated, when fluid therapy or other 
treatments, are not sufficient to reach perfusion goals and stabilization of the critically 
ill60,64,65,73,74,76,77,82-85.  
A single-center study of peripherally administered noradrenaline in sepsis from Thailand, the 
CENSER trial from 2019, reported that early initiation of noradrenaline lead to faster shock control 
than usual care, defined as following the Survival Sepsis Campaign recommendations60,86. 
Likewise, delayed initiation of vasopressor therapy in septic shock is associated with increased 
mortality.73 But even though the use of central venous catheter (CVC) has historically been deemed 
the safest option for infusion of noradrenaline, due to risk of extravasation and skin necrosis, 
placement takes time, and are sometimes not possible in the critically ill when compared to 
peripheral catheter placement.65,73,74,76,80,82-85,87-90 Initiation of vasopressor therapy through 
peripheral catheters, when compared to central venous access, lead to reduced time for initiation of 
therapy, and, importantly, with no increase in mortality risk.60,74,76 At the same time, complications 
and adverse events from use of vasopressor infusion through peripheral catheters is 
miniscule.64,79,80,84,91 Other catheter choices can include the use of midline catheters, intraosseous 
cannulas and PICC lines, all of which has been found with at least the same level of safety as 
peripheral catheters or CVC.92-96 
The CLOVERS trial64, was a multi-center randomized trial but failed to show lower mortality in the 
restrictive fluid therapy arm. This, however, was conducted in the United States of America, where 
treatment protocols and guidelines differ substantially from Scandinavia. 
CLOVERS reported 750 patients receiving vasopressor at any point during the trial, of which 500 
received the treatment through peripheral catheter at some point. Only 3 (0.6%) of these had 
complications, documented as extravasation, though no subsequent skin necrosis were observed. In 
contrast, 14 (3.9%) had a CVC placement with complications, including serious adverse events such 
as deep vein thrombosis (3), ventricular arrhythmia (1), atrial arrhythmia (7) and pneumothorax (1). 
CENSER have not specified adverse events related to peripheral lines for each group, and both 
groups had CVC inserted during the trial (43.8% vs. 46.1%). The early intervention group had 
significantly fewer events of reported cardiogenic pulmonary oedema (14.4% vs. 27.7% p=0.004), 
but all other adverse events were with non-significant difference between groups.  

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This may suggest that the early use of vasopressors through peripheral venous access may lead to 
improved outcomes for patients presenting in the ED with septic shock.  
 
1.5. Hyperlactatemia and lactate clearance in shock 
Lactate, under physiological conditions is a normal product of cell metabolism and is cleared by the 
liver. Lactate production can outpace its clearance leading to an increased blood lactate levels in 
shock. 97 98 99 100 Elevated lactate level, usually defined as > 2mmol/L,  is usually the result of 
anaerobe glycolysis, which is the body’s response to hypoxia and decreased tissue perfusion, but 
also can be derived from inefficient lactate clearance, an increase in protein degradation, or 
increased glycolysis, i.e. increased metabolic state that is associated with hypotensive shock. 101 102 
103 Even though lactate is often used as a parameter for diagnosis of sepsis and shock, patients still 
present with normal lactate levels in the early course of the conditions, still providing substantial 
mortality, though not as high as patients with hyperlactatemia.104 Repeated measurements of serum 
lactate levels of critically ill patients is used in clinical practice to monitor treatment efficacy, and as 
a guide to optimize treatment,  105 99 100 and considered a predictor of mortality 97,106 103 107 . As of 
today, there are different opinions regarding the optimal timing of these measurements, however 
most studies agree on that they should follow the time window of the cells to normalize with the 
return of normal perfusion and oxygen supplies. 99 Studies suggest that measurement of lactate 
levels need to take place at least 2, 6, 12 and 24 hours after initializing treatment 99,106. However, the 
frequency of measurements is based on the severity of the patient’s condition and can therefore 
differ significantly. This consensus does not consider whether fluid or vasopressor therapy as 
primary choice influence these changes.  
In addition, the choice of either arterial or venous blood gas analysis can differ between 
departments and countries. Even though arterial gas analysis is considered the best option for 
correct measurement, venous blood gas samples are well correlated for lactate measurement. 108 109 
110 111 112  However, venous punctures can be a better choice than arterial, when considering risk of 
the procedure including less pain and technically less demanding. 109,113 110 
 

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1.6. Biochemical, neuroendocrinal, hormonal and acid-base changes in 
critical illness  
Critical illness and especially shock imposes widespread systemic responses in the host organism 
including changes in biochemical, neuroendocrinal, hormonal and coagulation processes. 5,114-121 
These processes are usually vital parts of the human homeostasis and regulation but can pose risks 
if these intrinsic parts are malfunctioning. 114,119,120,122 The maintenance of hormonal and 
coagulation balance is critical in the treatment of shock, however, the understanding of how 
treatment using only fluids compared with supplementary noradrenalin infusion might influence 
these, is not fully established. 116-121,123-128 
A key component of sepsis and especially septic shock is the systemic inflammatory response 
syndrome where inflammatory cytokines are released resulting in an increase in 
Adrenocorticotropic Hormone (ACTH) concentration to improve hormone production of 
Adrenaline and Noradrenaline. This release results in increased blood pressure, heart rate and 
peripheral vasoconstriction to stabilize the cardiovascular demise. 115,117,118 
Other pathways, such as the Renin-Angiotensin-Aldosterone pathway, are part of the intrinsic 
regulation of blood pressure. Low blood pressure increases renal Renin release which in the end 
increases aldosterone release from the adrenal gland leading to renal salt and water retention. 117-120 
However, pro-inflammatory mediators decrease the secretion of vasopressin, and nitric oxide, 
subsequently decreasing the effect that angiotensin imposes on its receptors – thereby suppressing 
the compensatory mechanisms to hypotension. 114,115,117,118 Coagulation parameters can be 
destabilized in these critical conditions and lead to severe systemic responses such as disseminated 
intravascular coagulation (DIC) 125-128 with excessive changes to coagulation parameters 116,122,129 
while also leading to more severe disease presentations and outcomes for patients. 114,130,131 Due to 
the excessive impact on the organism, other factors have also been associated with both disease 
severity and possibly prediction of patient outcomes.132-138 Changes are especially seen in areas 
such as the cytokine system and signaling pathways, including changes in endocrine system  
especially for septic patients.132,134-136,138 In addition, recent research suggests a possible tool of 
diagnosing sepsis, which can be difficult to identify in certain situations, using flow-cytometry and 
immune cells.139 Even the use of micro-RNA evaluation in patients have been suggested as a 
possible pathway for better treatment precision and personalized regimens for the individual 
patient.140,141  

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Cells exposed to high metabolic stress secrete a higher number of extracellular vesicles. These 
extracellular vesicles contain mRNA, which can be used to identify its parental cell type. The EV 
RNA fingerprint in plasma and urine samples can therefore be used to identify possible host 
responses to critical illness and treatment regimens.142   
Shock can affect all these parts of the human organism and even though research have look 
extensively into these areas, a more profound understanding of how different treatment strategies 
might influence them are not yet fully established.  
 
1.7. Rationale for studying early initiated peripheral noradrenaline in 
the Scandinavian setting 
This study will provide evidence if early initiated vasopressor therapy can decrease to time for 
achieving shock control and subsequentially improve outcomes, such as avoiding ICU admission or 
reduce length of stay, for some of the most critically ill patients in the ED setting. Current studies 
shows that there exists a clinical equipoise in treatment of the patient group, but it’s tested in 
different organizational models and settings, which challenges the consideration and 
implementation of treatment recommendations in Scandinavian ED’s. Hypotension is a time-critical 
condition and improving the treatment of hypotensive patients might decrease mortality, morbidity, 
and ability to return to usual live and work. 
 
1.8. Systematic review of existing literature 
We performed a structured search of PubMed, EMBASE, CINAHL and the Cochrane Library for 
any relevant studies for treatment of shock with vasopressors in the ED through peripheral catheters 
in non-traumatic hypotension. The setting of the ICU or operation theatre is widely different from 
the average ED and are therefore not considered in our review.  
We also searched registers in clinical trial databases (Clinicaltrials.gov, EU-CTR and ANZCTR). 
We identified two currently completed studies, CENSER and CLOVERS64,86 and two studies 
currently recruiting patients, EVIS and ARISE.143,144 
 

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1.9. Choice of comparators with prior and on-going studies on early 
vasopressor therapy 
The CENSER86 study was a single-center study comparing early vasopressor therapy through 
peripheral catheters in patients with suspected sepsis with hypotension. Patients were randomized 
1:1 to either early noradrenaline (n=155) or standard treatment (n=155). The early vasopressor arm 
had a significantly higher proportion of patients achieving shock control within 6 hours after 
diagnosis (76.1% vs. 48.4%, odds ratio 3.4 (95%CI 2.09-5.53)) and the control arm presented with 
a higher quantity of adverse events such as cardiogenic pulmonary oedema, probably due to more 
excessive use of fluid therapy. There was no significant difference between the groups when 
comparing mortality or admittance to the ICU, but the study was not powered for these endpoints.  
The CLOVERS trial was a multi-center randomized clinical trial including patients in both ED, 
ward and ICU settings, assessing whether fluid therapy or early vasopressor therapy for septic 
shock, could improve patient outcomes, with a primary endpoint of mortality before discharge 
home by day 90.64 They found no difference between the intervention and control group with a 
mortality of 14.0 (11.6-16.4) in the restrictive fluid group with early vasopressor compared to 14.9 
(12.4-17.4) in the liberal fluid group.  
The CLOVERS study had several issues regarding generalizability. More than 12,000 patients were 
screened with only 1,563 randomized and 7,408 patients excluded due to fulfilling one or more 
exclusion criteria such as 1) more than 4 hours elapsed since inclusion criteria met (2,874 patients) 
or 2) having received more than 3 litres of fluid before screening (1,786 patients). Also, a total of 
3,303 patients met the eligible criteria, but were not enrolled due to issues such as 1) Unable to 
obtain informed consent (900 patients), 2) Patient or surrogate declined consent (887 patients), 3) 
physician refused patient participation (873 patients), 4) surrogate not available (565 patients), and 
5) not excluded but not enrolled (346 patients).  
These issues could cause a risk of selection bias, as alone more than 2/3 of patients were not 
enrolled due to time, fluid therapy received before inclusion (including pre-hospital fluid) or the 
lack of consent for any cause. One could theorise that the substantial number of exclusions before 
enrolment could have influenced the results.  
The ARISE144 and EVIS143 trials are actively recruiting and evaluate early vasopressor therapy in 
the emergency departments. Both studies investigate mortality where CLOVERS failed to show 
benefit in the restrictive fluid group. Our study will differentiate from these studies, as shown in 

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Table 1, due to not only including septic patients, but other patients with hypotension as well. Also, 
the participants will primarily receive vasopressor therapy in the ED through a peripheral venous 
catheter (PVC), as in the EVIS trial, but will not be compared to a group receiving delayed 
vasopressor therapy in the ED. Our target goals for treatment and primary outcomes differ.  
We therefore argue to randomize patients to either standard care alone compared to standard care 
and early vasopressor initiation through a peripheral venous catheter, using a pragmatic study 
design in a setting as close to current daily treatment algorithms in the ED. Current treatment 
options in the control group, are far more restricted than presented in other trials on vasopressor 
therapy. We can subsequently evaluate if patients can avoid ICU admittance if treated up to 24 
hours in the ED.  
 
 
 

Table 1: Overview of VASOSHOCK, ARISE and EVIS 
 
VASOSHOCK 
ARISE 
EVIS 
Inclusion criteria 
 Signs or suspicion of hypotension 
or shock (of any type such as septic, 
vasodilatory or hypovolemic not 
included in the exclusion criteria) 
defined as: 
a. SBP < 100mmHg or MAP < 65 
mmHg combined with lactate > 2.0 
mmol/L, 
b. Physician defined blood pressure 
for the individual patient combined 
with a lactate > 2.0 mmol/L 
c. Either SBP < 100mmHg or MAP 
< 65mmHg with obvious signs of 
shock with any lactate level 
evaluated by either two non-
specialist physicians (e.g. registrar 
medical doctors) or a specialist 
physician.   
SBP < 90 mmHg and lactate > 2.0 
mmol/L 
Either SBP < 90 mmHg or MAP < 
65 mmHg AND lactate > 2.0 
mmol/L 
Patient group 
Hypotension not related to 
cardiogenic, anaphylactic, 
neurogenic or haemorrhagic cause 
Septic shock 
Sepsis and hypotension 
Number of patients 
planned 
 
320 
1000 
3286 
Time to enrolment 
In the ED if patient received 
necessary fluid. 
Within 6 hours of presentation 
Within 12 hours of presentation 
Pre-randomisation 
fluid 
≥ 0.5L  
1 to 2L 
Up to 1.5L 

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Intervention 
Peripheral vasopressor or local 
standard of care  
Fluids or vasopressor according to 
study protocol 
Early peripheral vasopressor or 
standard of care in accordance with 
SSC or local guidelines 
Duration of 
intervention 
 
Up to 24 hours 
6-24 hours 
Up to 48 hours 
Target treatment 
goal 
SBP > 100 mmHg or MAP > 65 
mmHg or defined by physician 
Determined by physician 
MAP > 65 mmHg 
ED vasopressor use 
before trial 
 
No 
Yes 
Yes 
Primary outcome 
Proportion of patients achieving 
either SBP >100 mmHg or MAP > 
65 mmHg or a target blood pressure 
set by the treating physician at 90 
(±15) minutes after inclusion 
Days alive out of hospital at 90 days 30-day all-cause mortality 
 
 
 

2. Trial objectives and hypotheses 
2.1. Aim 
The aim is to investigate whether the use of early initiated vasopressor therapy (i.e., noradrenaline) 
compared to fluid therapy alone in non-bleeding hypotensive patients presenting in the ED can 
improve time to shock control and by that, reduce the need for ICU admittance.   
 
 
 
 

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3. Trial Design 
3.1. Overview 
This study will be a pragmatic,145,146 multi-center, superiority, randomized controlled trial, 
randomizing patients 1:1 to either the intervention group (early vasopressors in the ED) or control 
group (standard care in the ED). Hypotensive patients who received at least 500 ml fluid bolus prior 
to screening will be assessed for eligibility.  
3.2. Allocation and randomization 
Patients fulfilling all inclusion criteria and no exclusions criteria (see below) will be randomized in 
a 1:1 ratio using block randomization by random size of 2, 4, 6 or 8, stratified by trial site. 
Randomization will be conducted using the web-based randomization system provided in REDCap 
to ensure allocation concealment.147  
The investigators will access the randomization page using a unique QR code allocated for each 
trial site, directing to an online registry form. Each investigator will be registered for their specific 
trial site, and if applicable, for any other trial sites they are employed at (either full or part-time). 
Basic data will be entered from eligible patients prior to randomization, as described in section 9. 
Data collection and management. 
The randomization allocation sequence is generated by the OPEN data manager and stored securely 
in relation to the REDCap database. Only the data manager, or REDCap administrator, for the 
project have access to the allocation sequence if necessary. Individuals screening and commencing 
inclusion of patients in the trial, will not have access to the allocation sequence.  
3.3. Interventions 
Eligible patients will be randomized to receive noradrenaline starting at 0.05microg/kg/min and 
titrated to either SBP >100mmHg or MAP >65mmHg or a physician predefined blood pressure 
goal, up to a maximum dose of 0.15microg/kg/min.  
Route of initiation is preferred to be the first available secure route of infusion, usually a peripheral 
venous catheter (PVC), but other methods can be used if these are standard care. Other more secure 
access types, such as midline catheters, central venous catheters, peripherally inserted central 
catheters (PICC) is also allowed if these are standard care in the individual department, as long as 
the line is secure and with a minimal risk of extravasation. For trial  

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Decision for dosing regimen can be seen in section 6.2. Dosing regime and rationale for dosing 
levels.  
 
Monitoring of patients’ blood pressure is recommended with at least use of Non-invasive Blood 
Pressure (NIBP) every 15 minutes combined with continuous 3-lead ECG and peripheral oxygen 
saturation (SpO2) if they receive noradrenaline infusion. If department standard care includes the 
use of more invasive methods for blood pressure monitoring, such as arterial lines, these can be 
used as well without requiring concurrent use of non-invasive methods.  
 
When possible, down titration will be conducted if the goal SBP or MAP is still achieved. During 
the 24-hour intervention period, infusion of noradrenaline can be temporarily stopped and resumed 
within this timeframe. If temporarily stopped, the clinical staff should note time for this event, as 
well as reason on the CRF, and when the infusion is resumed, if pragmatically possible regarding 
external factors in the ED.  Noradrenaline infusion will be terminated fully if the patient stabilizes 
to the target values without the need for vasopressor therapy during the intervention period.  
Patients that require more than 0.15microg/kg/min or have signs of severe multi-organ failure 
requiring ICU treatment, will be consulted with the ICU team for admission to the ICU. 
There will be no restrictions on concurrent care and the infusion of noradrenaline can be supported 
by further fluid infusion, if the treating physician decides it is necessary for the patient in 
accordance with local guidelines.  
 
To ensure generalizability of the results, and due to the pragmatic nature of the study, the ordering 
and administration of vasopressors, including monitoring and registration of bedside clinical data, 
will be handled by the regular ED staff. Each trial site will have research staff employed either full 
or part time, that will assist in ensuring trial progression, inclusion, and answer questions from the 
ED staff regarding the trial in collaboration with the local site principal investigator.  
3.3.1. Termination of intervention  
Patients included in the intervention arm will be treated in the ED for up to 24 hours with 
administration of noradrenaline. If the patients are still requiring noradrenaline at 24 hours, the ICU 
consultant will be contacted for patient transfer to the ICU. The intervention is fully terminated 
when the patient is either discharged from the hospital, admitted to the ICU, is dead during the 

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intervention period, or consent is withdrawn. Intervention is also fully terminated if the patient is 
admitted to another department, except in the situation for other departments participating in the 
trial as described in department as described in section 3.3.3 Treatment during 24-hour intervention 
in other departments. 
 
3.3.2. Weaning of noradrenaline infusion during ED admittance 
During the 24-hour intervention period, patients can stabilize and therefore not require further 
noradrenaline infusion in the ED. If the treatment goals are reached, either set by usual blood 
pressure targets as protocolized or determined by the treating physician, the clinical staff can begin 
to lower and wean the vasopressor dose. This can be done by reducing the dose slowly by 0.01-
0.03microg/kg/min and closely evaluate the patient afterwards within the next 15 minutes. After 15 
minutes, the dose can be lowered further if criteria are met. If it is possible to completely wean the 
patient of the infusion, the intervention can be stopped, but it is allowed to resume the intervention 
within the first 24 hours of study entry if the patient is still present in the ED or in a department as 
described in section 3.3.3 Treatment during 24-hour intervention in other departments.  
Time of termination or recommencing should be clearly noted in the paper-CRF.  
3.3.3. Treatment during 24-hour intervention in other departments 
As local ED organisations are different across the country, not all ED’s are able to treat patients for 
up to 24 hours during their participation in the trial. This could possibly require that patients are 
either quickly weaned off the noradrenaline infusion risking hemodynamic collapse, or that further 
treatment even after a few hours would require ICU admittance. Due to these organizational 
restrictions, the trial allows continuation of the treatment at same hospitals departments if the 
following conditions are met: 
1. The department have sufficient staffing and capacity to treat and monitor the patients by at 
least the same minimum standard as the ED in the same hospital. 
2. Staff handling the early intervention of noradrenaline prior to complete wean off or 
necessary post 24 hours ICU admittance are educated in the same manner in the trial as the 
staff in the ED. 
3. The treatment protocol and standard operating procedures set by either the Sponsor or local 
Principal Investigator is followed as if the patients were still in the ED. 
4. The investigators at the local site can be contacted and necessarily evaluate the patients 

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when needed in accordance with the protocol. 
3.3.4. Early termination of intervention 
Participants in the trial can have the intervention terminated before full conclusion of the treatment 
period. This can include fully termination of participation in the clinical trial including data 
collection and usage as defined in section 9. Data collection and management and 10.4.4. Consent 
for participation. This is considered in the following situations: 
1. The patient or their legally designated representative withdraws their consent to participate 
prior to completing the necessary intervention. 
2. The patients next of kin, for countries where consent can be partly obtained from these, 
withdraws the consent for the patient to participate prior to completing the necessary 
intervention. This is only possible, if the patient are yet to provide consent for participation. 
3. The investigator for safety reasons finds it of best interest of the patient. 
In case of early termination of the trial participation and therefore treatment, the clinical staff and 
investigators must take appropriate steps to ensure the patients treatment and stability of their 
disease process during early weaning of noradrenaline. This can include quick transfer to the ICU 
for further treatment of their condition.  
Early termination of treatment should be clearly noted, including reason for early termination, in the 
paper CRF for the patient.  
3.4. Control group 
The control group will be receiving standard care as ordered by the treating physician according to 
local guidelines at the ED. Current Scandinavian practices are mentioned in section 1. Background.  
3.5. Blinding 
Blinding of vasopressor therapy with noradrenaline is deemed impossible due to expected quick 
response in blood pressure levels with infusion of the medication, compared to fluid therapy at these 
rates. Therefore, blinding is not considered possible for this study.  
3.6. Sub-studies 
The VASOSHOCK trial consists of several sub-studies applicable. The long-term follow-up study 
will be completed for all participants in VASOSHOCK. For other sub-studies, prior to 

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randomization, the investigators will register which, if any, of the specific sub-studies that the 
participant will be enrolled in. This is to ensure that participants are not selected for specific sub-
studies based on group allocation. Not all sites participate in these sub-studies.   
3.6.1. Sub-study 1: Long term follow-up 
A pre-planned long-term follow-up of patients will be completed after inclusion in the trial. This 
long-term follow-up will partly be from direct contact to the participants (e.g. by phone) and patient 
electronic medical records. The study will assess areas such as patient ability to live without 
caregiving from others, such as municipality homecare. See Appendices , appendix 6.  
 
3.6.2. Sub-study 2: Non-invasive hemodynamic monitoring of patients with 
hypotension and shock 
The aim of this study is to evaluate changes in hemodynamic parameters for patients with 
hypotension or shock receiving peripheral vasopressor therapy compared to standard fluid 
resuscitation. Hemodynamic parameters will be evaluated using non-invasive measurement of 
MAP, stroke volume (SV), CO and systematic vascular resistance (SVR) in patients admitted to the 
ED and enrolled in the VASOSHOCK trial. 
Patients in this sub-study will be monitored with usual non-invasive measurement of vital 
parameters as available in the ED as recommended in VASOSHOCK. Patients included in this sub-
study will furthermore be monitored using the HemoSphereTM monitoring system with the 
ClearSightTM (Edwards Lifesciences, Irvine, USA)148,149 finger cuff for non-invasive continuous 
hemodynamic parameters. Hemodynamic monitoring will be conducted from patient inclusion in 
the trial and until the end of participation in VASOSHOCK. 
 
Data from the monitor will be extracted and stored securely in either the eCRF or the trials’ secure 
electronic SharePoint site.  
 
3.6.3. Sub-study 3: Lactate normalization in hypotensive shock patients 
Patients included will have an arterial or venous blood puncture performed at study inclusion as 
required in the main trial followed by measurements at 2, 6 12, 18 and 24 hours after inclusion or 
until termination of the treatment period in the main trial. Each sample requires a collection of 1-

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2ml of blood, i.e. between 1 and 12mL of blood in total over the course of the trial. All samples are 
analysed using the departments’, or hospital laboratories’, usual equipment for these measurements.  
Data are then extracted and stored following the data collection methods. eCRF prior to analysis.  
 
3.6.4. Sub-study 4: Biochemical, neuroendocrinal, hormonal and acid-base 
changes in shock and hypotension 
Patients included will have venous blood samples drawn at the following time points: Baseline at 
inclusion, at 90 minutes and at morning rounds the next day, day 2 of admittance and day 5 if the 
patient is still admitted.  
Blood samples are drawn to be analyzed for pro- and anti-inflammatory proteins (interleukins, C-
reactive protein, tumor-necrosis factor alfa), hormones for hemodynamic regulation (adrenaline, 
noradrenaline, renin, angiotensin), coagulation factors (INR, APTT, antithrombin, thrombocytes, d-
dimer, fibrinogen, ROTEM), anabolic and catabolic hormones (cortisol, insulin, growth-hormones 
including the insulin-like growth factors), immune-profiling, flow-cytometry, micro-RNA, mRNA 
and acid-base measurements by either venous or arterial blood gas analysis.  
Blood samples at baseline and the next day’s morning round include blood drawn up to a total of 
66.5 mL at each time-point. Blood samples at 90 minutes include blood drawn up to a total of 36.5 
mL. Blood samples drawn at the morning round of day 2 and 5 each consist of up to 30 mL of 
blood at each time-point. In total up to 229,5mL blood collected over the course of 5 days from 
inclusion. Additionally, we will collect 1-2 ml of urine at each time point for additional analysis for 
the mRNA analysis, see section 3.6.4.1 mRNA. 
Samples will be stored locally at the trial site in a secure manner before either analysis or transfer to 
the research biobank. Samples requiring analysis shortly after collection due to inability of storage 
(such a coagulation parameters or acid-base measurements) will be analyzed at each trial sites 
laboratories or by using point-of-care diagnostics if needed. Blood samples eligible for storage not 
requiring immediate analysis are either rested a room temperature or cooled using either an 
applicable refrigerator or ice, then centrifuged before being frozen and stored in a freezer prior to 
transfer to the biobank. Analysis will then be completed either locally when the necessary facilities 
are available in the local laboratory or analyzed in hospital department laboratories for specialized 
analyses (such as interleukins or micro-RNA) or at specialized research laboratories at the 
University of Southern Denmark (for mRNA). Samples, other than samples not possible to freeze 

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and store or not possible to analyze locally, are expected to be analyzed at Odense University 
Hospital or their regional biochemical department at Vejle Hospital for tests not possible to analyze 
in Odense. Samples will be prepared and stored in the research biobank prior to analysis within the 
timeframe of the biobank’s lifespan and prior to biobank termination.  
 
3.6.4.1. mRNA from plasma and urine samples 
The mRNA from extracellular vesicles are isolated and sequenced from plasma and urine samples. 
Each sample requires 1-2ml of plasma or serum stored in a EDTA tube, and 1-2 ml for urine 
samples prior to being frozen to -80°C. Analysis is completed using the exoRNAeasy midi kit 
(QIAGEN, Hilden, Germany). The isolated RNA is sequenced to quantify the amount of RNA 
transcripts. The identified nucleotide sequence is only used to computational identify the origine 
gene. The RNA sequencing is completed using an Illumina platform (Illumna, San Diego CA, 
United States of America) and from this the specific RNA transcript quantity is identified from 
genes in the host, through dedicated software such as R project (https://www.r-project.org/). The 
RNA sequencing data are then analyzed to identify the correct quantity of extracellular vesicles of 
different cell types using a transcriptome deconvolution method.  
Through the methods applied in the trial, the total amount of mRNA is identified, but the specific 
sequences are not used as part of the analysis.  
 
3.6.5. Sub-study 5: Thermography changes in early treatment of hypotension 
and shock 
Patients included will have thermographic images taken and bed-side measurement of the capillary 
refill time done at inclusion and after 90 minutes. If possible, further images and capillary refill 
measurements will be conducted repeatedly (maximum once every hour) while the patient is 
included in the intervention period of the study.  
Data from the monitor will be extracted and stored securely in either the eCRF or the trials’ secure 
electronic SharePoint site.  
 

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4. Setting and patient population 
4.1. Setting 
Scandinavian ED’s admit a group of undifferentiated patients arriving either by prior evaluation 
from a general practitioner, by ambulance through the national emergency number or by self-
referral, though the latter is very uncommon. The physician staffing varies from each department, 
with most having a mixture of both consultants with specialization in Emergency Medicine and 
other specialties (Internal medicine, general surgery etc.).66,67,69,150 
The patients will be included under the regulation for “Acute drug trial” – See section 10.1.1. 
General considerations for specification.  
4.2. Eligibility criteria 
Patients admitted to the ED with signs or suspicion of hypotension or shock will be screened.  
4.3. Inclusion criteria 
1. At least 18 years of age  
2. Signs or suspicion of hypotension or shock (of any type such as septic, vasodilatory or 
hypovolemic not included in the exclusion criteria) defined as: 
a. SBP < 100mmHg or MAP < 65 mmHg combined with lactate > 2.0 mmol/L, 
b. Physician defined blood pressure for the individual patient combined with a lactate > 2.0 
mmol/L 
c. Either SBP < 100mmHg or MAP < 65mmHg with obvious signs of shock with any lactate 
level evaluated by either two non-specialist physicians (e.g. registrar medical doctors) or one 
specialist physician.  
3. Received at least 500ml of intravenous fluid before study inclusion (Including prehospital 
administration) 
4. Clinical Frailty Score (CFS) of ≤4. If CFS is ≥5 and the treating physician find the patient 
suitable for ICU admittance, the participant can be enrolled, if the on-call ICU doctor would 
accept the patient for ICU admittance. If the treating physician is unsure of ICU eligibility, 
regardless of CFS score, the patient should be consulted with the ICU consultant before study 
inclusion.  

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4.4. Exclusion criteria 
1. Cardiogenic, anaphylactic, haemorrhagic, or neurogenic shock suspected by the treating 
physician.  
2. Fertile women (<60 years of age) with positive urine human gonadotropin (hCG) or plasma-
hCG or women breastfeeding. 
3. Patient deemed terminally ill or with a severe co-morbid status resulting in non-eligibility for 
ICU admittance decided by either the treating physician or ICU consultant. 
4. Severe organ failure outside circulatory failure that requires immediate ICU admission.  
5. Known allergy to noradrenaline. 
6. Previously enrolled in the trial  
 
4.5. Co-enrolment 
The trial has no restrictions regarding co-enrolment in other trials.   
 

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5. Outcomes 
5.1. Primary outcome 
Proportion of patients achieving either SBP >100 mmHg or MAP > 65 mmHg or a target blood 
pressure set by the treating physician at 90 (±15) minutes after inclusion  
5.2. Secondary outcomes 
• Number of ICU free days alive within 30 days 
• Time without shock within 24 hours 
• 30-day all-cause mortality.  
• In-hospital all-cause mortality 
5.3. Tertiary and exploratory outcomes 
• Proportion of patients receiving vasopressor at any point within 24 hours.  
• Time to vasopressor initiation during hospitalization 
• Duration of vasopressor infusion during hospitalization 
• Re-admission for any reason within 30 days of inclusion 
 
• ED length of stay 
• Proportion of patients admitted to the ICU during hospitalization 
• Hospital length of stay 
• ICU length of stay during hospitalization 
• Need for mechanical ventilation (either invasive or non-invasive ventilation) within 30-days 
• Need for renal replacement therapy (continuous renal replacement therapy or dialysis) 
within 30-days 
• Organ support-free days within 30 days (defined as mechanical ventilation, vasopressor or 
inotropic therapy, or dialysis).  
• Amount of fluid therapy received within the first 24 hours   

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5.4. Safety outcomes 
• Proportion of patients developing pulmonary oedema at any point within 72 hours from 
randomization (Diagnosed by physician in accordance with local guidelines, e.g., clinical 
decision including evaluation with paraclinical imaging such as x-ray or lung ultrasound) 
• Proportion of patients developing acute kidney injury at any point within 72 hours from 
randomization (Defined as an absolute increase of creatinine ≥26.5µmol/L or ≥1.5 fold from 
baseline) 
• Proportion of patients experiencing extravasation of peripheral noradrenaline 
• Proportion of patients having serious complications due to extravasation (Defined as a 
serious complication fulfilling the criteria for a serious adverse reaction, e.g. skin necrosis 
necessitating surgical intervention) 
• Proportion of patients experiencing overdosing due to noradrenaline infusion in the trial 
(Defined as severe hypertension, and reflex bradycardia suspected by the staff or 
investigators) 
• Proportion of patients experiencing any SAE, SAR or SUSAR related to the trial 
intervention or procedures registered during the trial 
 
 

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6. Pharmacovigilance 
6.1. Choice of IMP 
The investigational medicinal product (IMP) for this trial will be noradrenaline (ATC-code 
C01CA03). An example summary of product characteristic can be found in Appendix 5. Current 
international guidelines suggest the use for noradrenaline as first choice in patients with shock not 
due to trauma. The IMP is already approved for clinical use and is used in the trial in accordance 
with this approval.   
 
6.2. Dosing regime and rationale for dosing levels 
Current guidelines in Denmark only sparsely recommend use of peripheral noradrenaline infusion 
and usually at low concentrations. As such, a clinical guideline at Odense University Hospital 
(Guideline 971736 updated 03-03-2023) describes the use of peripheral noradrenaline. This 
guideline does not describe the use of weight-based noradrenaline infusion, but a fixed dose 
infusion of 2mg/ml noradrenaline in 98ml isotonic NaCl unless the patient weighs 50kg or less. The 
suggested infusion rate is 15-30ml/hour with no statement of maximum recommended infusion rate. 
For a 70kg patient this would yield the following infusion rate. 
First dosage of mg/hr is derived from the following formula: 
𝑅 𝑥 𝐴
𝑉
 
R being rate of infusion, A being dose of the medication and V being total volume of the dose when 
mixed. This can be calculated based on the guideline: 
30 𝑚𝑙
ℎ𝑟𝑥 2 𝑚𝑔
100𝑚 𝑙
= 0.06 𝑚𝑔/ℎ𝑟 
Afterwards the dosage can be converted from mg/hr to mcg/kg/min to compare to the used dosing 
regimens in this trial: 
𝐷 𝑥 1000 𝑚𝑔
60 min 𝑥 𝑊 
D being dose in mg and W being patient weight in kg.  
We can therefore calculate the infusion rate mandated in this guideline for a 70kg patient receiving 
peripheral noradrenaline infusion: 

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0.06 𝑚𝑔 𝑥 1000 𝑚𝑔
60 min 𝑥 70
= 0.14 𝑚𝑐𝑔
𝑘𝑔/𝑚𝑖𝑛 
The presented guideline is based on recommendations from the manufacturer and a Danish 
publication on peripheral infusion of noradrenaline published in 2017.151 However, this publication 
is before further knowledge on the safety of peripheral noradrenaline were published.  
Recent studies64,84,89 suggest that dosing of noradrenaline through PVC show adverse event in 
extravasation, that might be unrelated to the dose given. E.g., Lewis et al.89 reported that 
extravasation was unrelated to dose level, but more related to length of peripheral infusion. The 
included trials reported a median max dose of noradrenaline of 0.13 mcg/kg/min and found no 
events of skin necrosis, even considering 8 events of extravasation.  CENSER86 conducted an 
intervention of noradrenaline infusion up to 0.05mcg/kg/min in the trial protocol, though they did 
report higher vasopressor doses received, including open label use. CLOVERS64 protocolized up to 
0.25mcg/kg/min for patients in the restrictive fluid group before providing further fluid therapy. 
Five hundred patients received peripheral vasopressors at some point during this trial. None of these 
trials reported any serious adverse events in relation to peripheral administration of noradrenaline. 
This is in relation to a higher and more severe observation of SAE for patients receiving central 
lines and noradrenaline infusion through these, including pneumothorax and arrhythmias requiring 
subsequent DC-conversion. Details on previous publications on the safety in peripheral vasopressor 
therapy is described in section 1.4. Early vasopressor therapy for hypotension and shock. The trial 
details for the intervention are specified in 3.3. Interventions. 
Choice of dosing regime, considering the above data, will be up to 0.15mcg/kg/min, to maximize 
effectiveness of the intervention while still ensuring high patient safety for trial participants. This 
dose is close to the current recommendation at Odense University Hospital as described earlier, 
even when taking newer data and safety assessments into consideration.  
The dosing regimen will prevent possible increased risk of extravasation complications with high 
dosing or the need for higher level of observation, such as the ICU, including supplementary 
treatment requirements when higher doses are necessary to stabilise the patient. 
 
6.3. Storage and handling of the IMP 
Most Scandinavian ED’s already store noradrenaline but are currently only accessed by the staff 
from the anaesthesiology department or ICU. Also, as the medication is fully approved by the 

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Danish Medicines Agency as well as The European Medicines Agency, storage of noradrenaline for 
the study does not require special permissions.  
As the medication is standard assortment in the hospital and department, no additional labelling is 
required, and the medication is delivered by the hospital pharmacies ready for mixing.  
To ease the access and use for the clinical personnel during the trial period, the trial implements the 
following considerations as necessary for each department: 
 
1. The medication will be stored in accordance with local department or hospital guidelines.  
2. If required locally for conducting clinical trials involving pharmacological products, the 
individual site is allowed to repackage the medication along with necessary utensils if 
deemed possible and allowing for easier handling for the clinical staff.   
3. If local packaging in clinical trials is used, the box has to be easy easily identifiable as 
storage of medication for the trial, by either use of colours or labelling so it is 
distinguishable to other medications or packages. The trial name and trial identification 
number are clearly marked on the box, including a list of stored contents.  
6.3.1. Infusion pumps 
Infusion pumps used in the trial is the usual infusion pump equipment that are routinely used in 
each department. However, the trial mandates the use of infusion pumps that have auto-stop 
functions which prevents unintentional infusion of medications if the infusion sets are disconnected 
from the infusion pump. If no such pumps are part of standard care, the trial site has to ensure the 
availability of these pumps for the trial including teaching and supervision for these to the related 
clinical staff participating in the treatment with noradrenaline. 
The infusion pumps used in the trial will be cleaned before use for another patient and are handled 
in accordance with local requirements.  
 
6.4. Preparation of the IMP 
The study medication will be prepared by the clinical staff in accordance with a trial specific 
standard operating procedure (SOP). The SOP will describe how the drug is mixed before being 
used for infusion, including type of fluid used for the solution and dose of noradrenaline in 
accordance with the individual patient weight.  

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Mixing of the IMP will follow table 2 for mixing with 100ml of either isotonic saline or isotonic 
glucose prior to administration. The used mixing dose used in the trial is derived from the standard 
guidelines from the intensive care unit and operating theatres at Odense University Hospital. As this 
trial is a low-intervention trial, see section 10.3 Low intervention trial, the staff will register patient 
weight, the dose of NA used for the individual patient, time and infusion rate during infusion of NA 
the paper-CRF. Batch numbers are registered as part of the local standard safety procedures for 
pharmaceutical products to ensure full traceability, if necessary, in cases such as recalls from the 
manufacturer. The IMP is mixed just prior to administration and the timing will therefore not be 
registered directly in the trial, but only on the labels for mixed medications in conjunction with any 
other registrations following local standard procedures.   
 
6.4.1. Table 2: Noradrenaline mixing dose 
IV infusion 
Infusion concentrates 
Noradrenaline 1mg/ml, vial or ampoule of 10ml  
Medication shelf life 
Infusion has a shelf life after mixing of 24 hours at 
room temperature.  
Administration 
Dosing through infusion pump. 
Mixing dose for infusion through 
infusion pump 
0.06mg x patient weight in kg mixed with isotonic 
NaCl or Glucose to a total volume of 100ml.  
1ml/hour = 0.01 mcg/kg/min 
Weight 
(kg) 
Noradrenaline (mg) 
Noradrenaline (ml) 
Isotonic NaCl or Glucose 
(ml) 
30 
1.8 
1.8 
98.2 
35 
2.1 
2.1 
97.9 
40 
2.4 
2.4 
97.6 
45 
2.7 
2.7 
97.3 
50 
3.0 
3.0 
97.0 
55 
3.3 
3.3 
96.7 
60 
3.6 
3.6 
96.4 
65 
3.9 
3.9 
96.1 
70 
4.2 
4.2 
95.8 

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75 
4.5 
4.5 
95.5 
80 
4.5 
4.5 
95.5 
85 
5.1 
5.1 
94.9 
90 
5.4 
5.4 
94.6 
95 
5.7 
5.7 
94.3 
100 
6.0 
6.0 
94.0 
105 
6.3 
6.3 
93.7 
110 
6.6 
6.6 
93.4 
115 
6.9 
6.9 
93.1 
120 
7.2 
7.2 
92.8 
125 
7.5 
7.5 
92.5 
≥130 
7.8 
7.8 
92.2 
 
6.5. Termination and destruction of the IMP 
When the intervention is terminated, either due to stabilization of the patient or admittance to the 
ICU, the end of treatment should be noted on the paper-CRF. These data will be transferred to 
REDCap with the rest of the paper-CRF data as detailed in section 9.1. Data collection methods and 
a total dose is calculated in the REDCap database.  
When the drug is terminated (including necessity to change utensils with new filled syringes), any 
remaining drug will be stashed in the departments storage for medical waste. Boxes are handled 
according to local guidelines including collection for future destruction.   
 
6.6. Choice of infusion route 
Any type of secure infusion route for medication infusion is allowed in the trial, if they are part of 
the departments standard care. This includes catheters such as midlines, PICC and central venous 
catheters. Intravenous access may also be used for a short period of the time prior to achieving a 
more secure access route.  
All lines should be secure for safe infusion of the medication with a minimal risk for 
extravasation.92-96 For PVC use, the trial requires that the departments follow the considerations as 
explained in 6.7 Insertion of peripheral catheters. 

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6.7. Insertion of peripheral catheters 
Insertion of PVC should be with a high assurance of correct in-vessel placement, therefore, the 
following considerations should be considered during placement before and during noradrenaline 
infusion: 
1) The placement should be done in a preferable large, more central vein in the arm (e.g. close 
to the fossa cubiti) and not in a small superficial vein (e.g. on a small vein at the dorsum of 
the hand). 
2) If there is any sign of venous puncture with outflow of blood or fluid when flushing, this 
vein should not be used for the infusion site. 
3) US guided placement of PVC for infusion should be done in a more superficial, rather than 
deep vein, due to easier evaluation of extravasation.  
4) Flushing should be able to be completed with ease after placement before infusion start.  
5) If the PVC shows signs of extravasation after infusion start, the PVC should be terminated 
and another one placed sufficiently, before resuming the infusion in the new PVC. 
 
6.8. Suspected extravasation 
There is a risk of extravasation of noradrenaline, which is a leakage of a drug into the tissue 
surrounding the catheter. This is, however, a rare complication, but one that potentially can cause 
subsequent skin necrosis of the affected area or limb. The current evidence suggest that report of 
patient harm is minimal.74,80,84,87,90,91,152,153. This risk has not previously been studied in the 
Scandinavian ED setting, and this study will be the first one to address the issue in this population. 
Therefore, it is necessary to evaluate catheter placement and quality throughout the intervention 
period and handle any signs or suspicion of extravasation. 
Clinical personnel should suspect extravasation if the patient reports pain or itching or if there is 
sign of pallor, oedema, or erythema at the infusion site. When suspicion of extravasation is 
maintained, the following actions are recommended: 
• Stop the infusion. 
• Disconnect the line from the PVC 
• If possible, attempt to aspirate up to 5 mL from the PVC 

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• Remove the PVC and apply dressing. 
• Mark the site of suspected extravasation 
• Inform treating physician. 
Supplementary therapy can be: 
• Elevation of arm to reduce swelling 
• Involve surgeon if there is a concern of skin vitality 
• Analgesia if necessary and applicable 
The suspected extravasation should be noted on the paper-CRF, uploaded to the eCRF as well as 
reported to the Sponsor as a serious adverse event.  
 
6.9. Unintended overdose of noradrenaline 
Noradrenaline overdose can cause severe hypertension, and reflex bradycardia. Patients can 
experience extreme headaches, photophobia, retrosternal pain, pallor, intense sweating, and 
vomiting, while clinical related issues are increased peripheral resistance or reduced cardiac output. 
If there is sign and suspicion of a serious adverse reaction, the following actions are recommended: 
• Stop in the infusion. 
• Disconnect the line from the PVC 
• Attempt aspiration of 5ml from the PVC. 
• Remove cannula and apply dressing.  
 
Handling of patient symptoms is done in relation to usual supportive care in accordance with local 
guidelines (E.g., analgesia for pain).  
Events are registered as described in 7. Safety and harm. 
 

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7. Safety and harm 
7.1. Definitions 
Adverse Event (AE): An untoward medical occurrence after exposure to a medicine, which is not 
necessarily caused by that medicine. 
 
Adverse Reaction (AR): All untoward and unintended responses to an investigational medicinal 
product related to any dose administered.   
 
Serious Adverse Event (SAE): An untoward medical occurrence after exposure to a medicine, 
which is not necessarily caused by that medicine: 
1. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
2. Results in persistent or significant disability or incapacity 
3. Results in a congenital anomaly or birth defect 
4. Is life-threatening 
5. Results in death. 
 
Serious Adverse Reaction (SAR): An adverse reaction that: 
1. Requires inpatient hospitalisation or prolongation of existing hospitalisation, results in 
2. Results in persistent or significant disability or incapacity 
3. Results in a congenital anomaly or birth defect 
4. Is life-threatening 
5. Results in death. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR): A serious adverse reaction, the nature, 
severity or outcome of which is not consistent with the reference safety information. 
 
7.2. General considerations and risk proportionate approach 
Inclusion in the intervention group should be done with high respect to potential adverse events and 
reactions of the therapy. As vasopressor therapy currently is not routine therapy in Scandinavian 
EDs, the clinical personnel will receive education in the handling, use and evaluation of the therapy. 

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Also, the clinical personnel will have specific areas to assess during the study regarding possible 
adverse effects of the intervention. 
The trial will use noradrenaline from any manufacturer that supply this to the individual trial site. 
The summary of product characteristic of Noradrenalin “Fresenius Kabi” is presented in Appendix 
5 as the reference safety information of the IMP, but other manufacturers equivalent noradrenaline 
solutions are used following local pharmaceutical storage.  
 
The studied patients are critically ill with hypotension and shock. Therefore, events regarding 
deterioration of this patient group will not be considered an adverse event due to the intervention. 
Fatal outcomes are expected and are therefore also an expected known risk regardless of treatment 
protocol.5-8,60,154 Noradrenaline is commonly used in different treatment settings, including in the 
setting of shock conditions, through peripheral lines, as mentioned in section 1.4 Early vasopressor 
therapy for hypotension and shock. This administration route for noradrenaline has been proven 
safe if handled correctly. Current evidence has established that risk of adverse events from 
peripheral infusion is even lower than for central venous catheters.74,79,80,84,87,89,90,152,153,155,156  
In previous trials investigating noradrenaline as an intervention, the occurrence of SAE and SAR 
were significantly lower than in the standard care groups. As such, the CENSER trial had more 
patients in the standard care arm experiencing cardiogenic pulmonary oedema, 27.7% vs. 14.4%, 
RR 0.70 (0.56-0.87) and new onset cardiac arrhythmia, 20% vs. 11%, RR 0.74 (0.56-0.94) with no 
difference between other SAE or SAR (such as skin necrosis, limb or intestinal ischemia).86 The 
CLASSIC 2 trial investigated the use of restrictive versus liberal fluid therapy regimes randomizing 
a total of 1554 participants in the ICU admitted for septic shock. There were no difference in SAE 
or SAR with the different fluid therapy approaches.61 The CLOVERS trial had comparable 90-day 
mortality, with no significant difference between groups for ventricular arrhythmias.64   
 
As this trial is a low-intervention trial, see section 10.3. Low intervention trial, as the infusion rate 
is low, see section 6.2. Dosing regime and rationale for dosing levels and as noradrenaline is not a 
medication with strict reporting obligations, the trial will implement a risk proportionate approach 
in the trial.1,157 
The risk proportionate approach follows the current recommendations provided by the Danish 
Medicines Agency in accordance with the EU regulation for low intervention trials.1,158  

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This approach will specifically include registration of events and reactions related to peripheral 
noradrenaline infusion as well as possible overdose.74,79,80,84,87,89,90,152,155 No other AE, AR, SAE or 
SAR as described in the SmPC is required for reporting to the Sponsor.  
Investigators will be able to report any SAE to the Sponsor immediately, and not later than 24 hours 
from such occurrence, at their own discretion. This includes any SAE that the investigator deems 
necessary to report though not predefined as stated in section 7.3 Assessed adverse events and 
reactions. 
The Sponsor will assess and follow up on any reports from investigators and include these in the 
annual safety report. All SUSARs will be registered and reported to the authorities. Apart from 
investigator reported events and all SUSARs, only the predefined SAE or SAR will be registered 
and reported to the authorities. See section 7.7 Reporting. 
7.3. Assessed adverse events and reactions 
7.3.1. Noradrenaline extravasation 
The following will be reported to the Sponsor as a potential SAE or SAR: 
• Extravasation of noradrenaline infusion  
• Skin necrosis at infusion site 
Extravasation of noradrenaline will be reported to the Sponsor following the procedures for SAE 
reporting, as this requires the investigators to report any extravasations to the Sponsor within 24-
hours. The subsequent assessment from the investigator and Sponsor might downgrade the 
extravasation event to an adverse event or reaction, if the event does not fulfil the criteria as 
described in 7.1 Definitions. This is implemented so the Sponsor always have oversight on potential 
risk issues mandating changes in oversight or safety handling during the trial.  
Skin necrosis is always considered a SAR if identified due to extravasation from the trial 
intervention. 
7.3.2. Suspected or evident overdose of noradrenaline 
The occurrence of the following will be reported to the Sponsor as a potential SAE or SAR: 
• Severe hypertension in combination with severe bradycardia with suspected or evident 
overdose of noradrenaline (Defined as a sudden onset blood pressure levels ≥180/110 
mmHg in combination with a pulse < 40 beats/min) 

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7.4. Suspected Unexpected Serious Adverse Events (SUSAR) 
If, at any point, the investigators are suspecting and unexpected serious adverse event (SUSAR) in 
either group, they are obligated to report this to the Sponsor within 24-hours following the 
procedures described in section 7.7. Reporting.  
 
7.4.1. Fluid treatment 
Fluid administration volume as well as outcomes such as acute kidney injury and pulmonary 
oedema are part of the outcome assessment described in section 5. Outcomes. 
As decisions on fluid treatment for both the intervention and control group is not provided by the 
trial or protocol, we will not evaluate any AE, AR, SAE or SAR in relation to these treatments 
unless the event is a possible SUSAR.  
 
7.5. Follow-up period for adverse events and reactions 
The assessment and registration of adverse events will be handled for noradrenaline infusion from 
inclusion to end of intervention, defined as 30 minutes after full termination of the noradrenaline 
infusion in the ED or applicable departments as described in 3.3.3 Treatment during 24-hour 
intervention in other departments. If a patient is transferred to the ICU by ICU staff (e.g. ICU 
registrar or attending), while still receiving peripheral noradrenaline, the assessment will be 
terminated as soon as the patient leaves the ED, or related department participating, and treatment 
responsibility will be handled by the ICU staff in accordance with local guidelines. If escorted by 
the staff administrating the intervention, the assessment will be terminated as soon as the patient 
arrives at the ICU and patient responsibility is transferred to the ICU staff.  
 
7.6. Registration 
Registration of SAE, SAR or potential SUSARS as described earlier will be completed by direct 
contact through e-mail, telephone or REDCap to the Sponsor. The Sponsor or investigator will then 
register these in the REDCap database if this was not initially completed.  

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7.7. Reporting 
Any previously stated and observed SAE or SAR during trial intervention will be reported within 
24 hours of occurrence to the Sponsor. Sponsor will evaluate if the SAE is a SAR or SUSAR, and 
report SUSAR to the central European register EudraVigilance within 7 days if fatal or life-
threatening, and 15 days for other SUSAR. A follow-up will be completed by the Sponsor no more 
than 8 days after reporting and will inform if the follow-up shows either life-threatening or fatal 
SUSAR. If the SUSAR poses risk to continuation of the trial- due to patient risk concerns, the 
Sponsor will inform all trial sites immediately.1,159 
Once a year, the Sponsor will submit an annual safety report to CTIS including a list of all SAE, 
SAR or SUSAR that have occurred on all sites. The annual safety report will describe the rules of 
registration and reporting of adverse events as described in this protocol. The annual safety report 
includes a risk-benefit assessment for all trial participant and will be included in the overall risk 
assessment.1  
 
 
 

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8. Sample size and statistical analysis plan 
8.1. Sample size calculation 
Our sample size calculation is based on data from the CENSER trial.86 The median time from 
“initial treatment to achieving the target of mean arterial blood pressure + tissue perfusion goal” for 
the intervention group was 4h:45 min and 6h:02 min for the controls. Given this difference, and 
considering a log normal distribution of the data, an alpha value of 0.05, and power of 90%, a 
sample size of 80 persons per groups is necessary.160 Due to the nature of our primary outcome, 
including a higher blood pressure target and allowing the treating physicians to individualize 
treatment goals for the patients, we will include a larger number of patients, as it is not possible to 
calculate the specific sample size for this end goal specifically. Also, powering the study towards 
preventing patients being admitted to the ICU is not sufficiently possible, as current data and 
previous studies has not evaluated this. We therefore plan to include 160 patients in each group 
(320 in total). This will also prevent skewing of data due to patient dropout or loss to follow-up.  
 
8.2. Statistical analysis plan 
8.2.1. General considerations 
Primary outcome will be presented as numbers (proportions). Secondary and tertiary outcomes (see 
above) will be presented as either numbers (proportions) for categorical values or mean (SD) for 
numerical outcomes. Continuous variables will be analysed using a parametric test such as a paired 
t-test or Pearson Correlation and for categorical values such as the chi-square test or Fisher exact 
test, where appropriate. The primary outcome and mortality will also be presented using Cox 
regression and Kaplan-Meier curves. Our main analysis will be intention-to-treat with per protocol 
as sensitivity analysis. 
Patient inclusion and exclusion will be illustrated in a CONSORT flow diagram. See Appendix 1 
for CONSORT flow chart draft.  
A full statistical analysis plan will be described before the final patient has been included.  

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8.2.2. Missing data 
Missing data will be reported in all relevant publications. We do not expect missing data regarding 
the primary outcome of the trial or key secondary outcomes. We do expect some missing data in 
other outcomes, as well as missing data or loss to follow-up for the long-term outcomes in the trial, 
either due to the death of the participant before the follow-up, or due to unavailability of direct 
contact. We do not expect missing data for SAE, SAR or SUSAR. 
 
 

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9. Data collection and management 
9.1. Data collection methods 
Data collection will be completed and managed using a secure web-based software platform 
REDcap (Research Electronic Data Capture) hosted at University of Southern Denmark via OPEN. 
All data will be entered using the secure web-form and from there extracted for data management. 
Data entered during randomization are cross checked during identification of the patient. All data is 
entered from the paper-CRF to the e-CRF. 
  
The investigators will enter limited data into the REDCap database prior to randomization, this 
includes the date and time of screening.  
Bedside collection will be completed using a paper Case Report Form (CRF) or collection of data 
throughout the patients’ treatment period of up to 24 hours. The paper-CRF will include data as 
mentioned under section 9.4. Data to be collected. All used paper-CRF (Partly or fully completed) 
will be stored locally as specified under section 9.3. Data management .  
 
9.1.1. HemoSphere™ data 
Data collected using the HemoSphere™ monitor for each participant will be extracted as an 
electronic file for each participant will be stored in the secure SharePoint site prior to data analysis. 
These data will not be entered in the eCRF.   
 
Further data will be collected using relevant national registries and electronic patient records, as 
well as follow-up data from the individual patient. The data will, when applicable, be either 
manually entered in the eCRF or sampled into the database. 
 
9.2. Participant retention and ensuring complete follow-up 
For inclusion in the study and participant retention, the study will include relevant outcomes that 
can be extracted from the participant’s personal health record and relevant national registries. Vital 
parameters, fluid type and amount of fluid given will be captured in the eCRF extracted from the 
patients’ medical records or monitors used during treatment.  

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9.2.1. Replacement of data from participants no longer enrolled in the trial 
Patients included in the trial, that subsequently withdraws consent for participation can decide either 
to only accept the use of data up until their withdrawal or if all data should be withdrawn from the 
trial participation. If the patient dies during the trial without providing consent, the data from the 
patient will be used in accordance with the trial protocol unless the deceased participants legal 
representative objects to use of the participants data.  
9.2.2. Replacement of participants withdrawn during the trial 
With the current planned participant inclusion of 320 patients, risk of patient withdrawal 
influencing the trial should be minimal. If all data are withdrawn during the interventional trial 
period by the patient, we will replace with one new randomization, but do not expect to replace 
patients with partly complete data in the trial. If we see a part dropout of ≥20% i.e., at least 64 
patients, the steering committee will decide if more patients will be needed for completion of the 
trial.  
 
9.3. Data management 
Data will be stored on a secured electronic database through REDCap via OPEN at Odense 
University Hospital, Denmark. All access to data will be logged on a person level complying with 
the European code for handling person data and according to national law161,162.  
Relevant parameters for patients during inclusion, exclusion and randomization will be entered 
bedside by the clinical staff and investigators. Screening of patients will be conducted using a 
screening log for each trial site, where all patients screened will be registered as described in section 
10.4.3. Screening and enrolment. Only patients fulfilling inclusion criteria will be identified on the 
log using the generated unique patient identify number in REDCap. Patients not included, and 
therefore not randomised, will be registered anonymously with only age, gender and which in- and 
exclusion criteria applied at the time of screening.  
 
The eCRF in REDCap for all data will be handled by either the trial sites principal investigator, 
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relevant information in the patient’s electronic health records after study inclusion, supplemented 
with data extracted from relevant registers to ensure full data records in the eCRF.  
 
The paper-CRF will be used during the trial period of up to 24 hours bedside, during the patient 
treatment. When the trial period is completed, for any reason, the paper-CRF will be stored locally 
in a secured locker in the department in accordance with applicable national law.  
The Principal Investigator, site investigators or dedicated research staff at each trial site will enter 
the recorded data form the paper-CRF to the eCRF. Data will be stored for at least 25 years after 
study inclusion as required by the EU regulation.1   
 
Blood analyses that are drawn and analysed during patient treatment are handled according to local 
guidelines and registration. The analysis data are entered directly into the eCRF or extracted 
electronically from the electronic patient record before merging to the eCRF or uploaded and stored 
in the secure SharePoint site.  
9.3.1. Data access 
Each patient will be identified in REDCap by both their CPR number and a unique trial 
identification number if included in Denmark. Patients included in Sweden will be identified in the 
REDCap database by their unique trial identification number and can be identified locally from the 
local trial identification log only accessible at the specific site. During the trial period, the Sponsor 
and Coordinating Investigator will have access to the entire database, while principal investigators, 
research staff and other employed study personnel will have access to data from their own sites. 
Clinical staff, who conduct inclusion, allocation, and treatment of patients under guidance and 
supervision of the principal investigator, will have access to the REDCap database for the patients 
they include. Access to the REDCap database is handled by individual login credentials with 
mandated multi factor authentication. The GCP unit, regulatory agencies and other relevant entities 
will have direct access to all relevant trial data as needed.  
 
 

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9.4. Data to be collected 
9.4.1. Data collected bedside on the paper-CRF 
• NA infusion dose concentration, including time of infusion start and termination and change 
of dosing. 
 
9.4.2. Data collected from the registered safety reporting or electronic patient 
records 
• Extravasation event (Time, duration, current infusion dose before termination, signs of 
necrosis, treatment for extravasation) 
• Severe hypertension and reflex bradycardia (Time, duration and further investigation or 
intervention if undertaken) 
• Any necessary media for continuous evaluation of the safety event (Such as photographs of 
extravasations) 
• Any other reported SAE including potential SUSAR. 
 
9.4.3. Data extracted from the medical records and bedside, including from 
patient monitors for either identification log, papir-CRF, data entry 
directly in the eCRF or storage in the secure SharePoint site. 
• Patient social security number or applicable unique patient identifier 
• Time of ED arrival including length of stay 
• Time of screening 
• Time of randomization 
• SAE, SAR and SUSAR and all necessary registrations in relations to these 
• Vital parameters up to 24-hours post randomization 
• Fluid administration time, type, and volume (mL) up till 24 hours post randomization 
• Time of death, if applicable, from inclusion and up to 1 year 
• Re-admission from inclusion and up to 1 year 
• Any admission to the ICU including length of stay of each admission within 30 days 

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• Hospital admittance including length of stay within 30 days 
• Each initiation of mechanical ventilation (either invasive or non-invasive) including time of 
initiation, duration, and termination within 30 days 
• Need for renal replacement therapy within 30 days 
• All blood sample analysis measurements (either venous, arterial or capillary) up to 72 hours 
post randomization 
• Development of acute kidney injury up to 72 hours post randomization (Defined as an 
absolute increase of creatinine ≥26.5µmol/L or ≥1.5 fold from baseline) 
• Development of pulmonary oedema up to 72 hours post randomization (Diagnosed and 
registered in the patient medical records by physician in accordance with local guidelines, 
e.g., clinical decision including evaluation with paraclinical imaging such as x-ray or lung 
ultrasound). 
• EQ-5L-5D163,164 level at inclusion, or as soon as possible and at 1-year. 
• Need for home nursing care or nursing home within 1-year 
• Re-admission within 30 days post randomization 
• Charlson co-morbidity index at ED arrival  
• Co-existing conditions at trial inclusion (e.g., diabetes)  
• Source of infection (if investigated, e.g. blood urine cultures) 
• Patient weight and height 
• Diagnoses during the ED and hospital stay, including any follow-up visits within 30 days 
 
9.4.4. Data collected in the screening log 
• Screened patients not included in the study will be registered in the screening log with the 
following: 
o Age 
o Gender 
o Reason for not reaching inclusion and therefore randomization 
 

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9.4.5. Data collected from the HemoSphere™ monitor 
• Blood pressure (Systolic, diastolic and mean) 
• Stroke volume 
• Stroke volume index 
• Stroke volume variation 
• Pulse pressure variation 
• Cardiac output 
• Cardiac index 
• Systematic vascular resistance 
• Systemic vascular resistance index 
Including specific date and time of each measurement. 
 
9.4.6. Data collected from blood or urine samples 
• Blood or urine analyses parameters measured in the sub-studies at the site laboratory, point-
of-care diagnostic equipment or from samples collected in the research biobank 
 
9.5. Reporting of the summary of results 
As soon as possible and no more than 1 year after the End of Trial, the Sponsor will upload the 
results to CTIS for the trial including a layman’s resume as required in the EU regulation.1 

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10. Ethical considerations 
The study will be submitted to the European Medicines Agency (EMA) through CTIS and from 
there assessed for the applicable parts of the protocol, including ethical committee review as 
applicable by each member state concerned. It will be conducted under the rules for research in 
emergency situations as described in section 10.4.2 Trial-specific procedures. The research protocol 
is written in accordance with the SPIRIT guidelines and the trial results will be reported following 
the CONSORT guidelines.165,166 The study will be registered in both the European Clinical Trials 
Information System (CTIS) and Clinicaltrials.gov. 
The trial will adhere to the revised Declaration of Helsinki167 as well as European and National laws 
as applicable, including following regulations on data protection and security in accordance with 
GDPR regulations1,161,162.  
 
10.1.  Research in shock and hypotension 
10.1.1. General considerations 
Shock and hypotension are emergent and critical conditions for patients and even though the 
conditions and treatments have been researched extensively, the mortality remains high.5,56,60,73,77 
Current guidelines considers fluid therapy as a first line treatment before initiation of vasopressor 
therapy, though the newest guidelines from the SSC mentions consideration for early initiation of 
vasopressor therapy.60,65,75-77 Currently, the optimal time for initiation of vasopressor therapy has 
not been fully established, but it is reasonable to expect, that early stabilization of patients could 
potentially lead to shorter LOS, duration of the critical condition and reduced risk of complications 
due to excessive fluid therapy.11,12,62,75,77,154 Current evidence does not address this, as early ED 
stabilization and therefore, possibly, decrease the necessity for ICU admittance among this patient 
group is evaluated in settings where vasopressor treatment initiated in the ED, will deem a quick 
admittance to the ICU.64,86 ED initiated vasopressor therapy has been used for several years, and are 
therefore used to earlier initiation if deemed necessary by the treating physician in countries such as 
the USA, Canada and United Kingdom.65,73,74,76,85,88,168 With the current organization and guidelines 
in Scandinavia, especially considering the use of fluid therapy for hypotension in the EDs, there is a 
unique opportunity to see if early initiated vasopressor therapy can improve patient outcomes. This 
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by that reduce LOS and less admittance to the ICU. This approach might not be feasible from a 
patient safety standpoint in countries with established usage of ED vasopressors, as this could 
potentially lead worse outcomes. Subsequently, it could lead to better understanding of more 
restrictive fluid approaches, if this therapy is lowered by the clinical staff due to earlier shock 
control, and therefore, possibly reduce the risk of complications from fluid overload. 
 
As the patient group is frequent in the ED6,9, we consider this trial of great interest to the general 
society and public, not just for the potential benefit to the individual patient, but also considering 
the extensive economical costs of ICU treatment compared to treatment in the ED or other hospital 
departments.   
 
Research in shock and hypotension provides challenges in ethics and patient consent. This is due to 
several reasons: 
1. Patients are acutely and critically ill, often with impaired cognition due to low blood 
pressure and, consequently, reduced blood perfusion to the brain. Additionally, patients in 
shock due to conditions such as sepsis can have bacterial toxins and inflammatory responses 
that may result in cognitive deficits until the underlying sepsis is controlled.169-171 
2. Patients may experience significant distress and anxiety due to the urgency of their situation, 
including rapid ambulance transport and the overwhelming environment upon arrival in the 
ED resuscitation area, where multiple healthcare providers simultaneously perform clinical 
assessments and initiate emergency interventions to stabilize their condition  
3. Treatment for the condition requires prompt and swift decision and initiation, limiting the 
possibility for obtaining informed consent from the patient extensively.  
4. Patients might be awake, while not being mentally present in a way to consider the 
information necessary to provide consent and are at a high risk of not having any 
remembrance of the situation when their condition is stabilized. 
 
Due to the necessity of research in improving both mortality and related outcomes in these 
conditions, there are no other patient groups, who can be used as a substitute in the research area for 
a similar intervention in their early stabilization period. Therefore, this trial will be conducted as an 
“Acute Drug Trial” where enrolment will be carried out without prior consent before inclusion, 

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randomization and treatment initiation. The specific procedures for obtaining consent post-
randomization are described in section 10.4 Informed consent procedures. 
 
10.1.2. Research Biobank 
A research biobank will be established at Odense University Hospital, and if necessary, additionally 
at local sites prior to transport to Odense, to store blood samples taken in the sub-studies. This 
biobank is only applicable for patients included in Denmark and no samples for the biobank will be 
collected outside Denmark. Blood samples not directly analyzed at the trial site of the included 
participants, will be stored in the biobank until all samples from all participants have been collected. 
Hereafter the samples will be analyzed. The blood samples stored in the research biobank will be 
destroyed no later than 5 years after the last patient’s last visit. When all samples are destroyed the 
research biobank will then be terminated.  
 
10.1.3. Collection of venous or arterial blood samples 
This sub-study collects blood samples with a total expected volume of 229.5 mL over 5 days 
different time-points in one sub-study and between 1-12ml of blood in the lactate sub-study. 
Collection of blood samples can pose risks during collection, both with minimal patient impact 
other than small hematomas, but also with small risk of more severe complications.172,173 However, 
to minimize these risks, the blood samples will, if possible, be collected at the same time as routine 
samples are collected from the participants. This will not always be possible due to inclusion and 90 
minutes samples are not necessarily drawn at the same time as routine tests, but samples collected 
during the next day’s morning round are. Blood samples will be collected by educated personnel 
from the clinical biochemistry laboratories at the trial sites, or by medical students with thorough 
education on the technique prior to performing the procedure. If venipuncture is deemed as a 
possible complicated procedure due to the participants clinical status, trained staff in ultrasound 
guided vein and arterial puncture procedures can assist the designated staff to improve success 
rate.173 All personnel collecting the blood samples will follow the local guidelines for performing 
the procedure, including recommendations provided by the hospital on the safety to minimize risk 
and harm in the participants.  
Collection of blood samples in critical ill patients are a frequent procedure to either diagnose or 
monitor their condition. A total of 229.5 mL of blood is a small sample for the patients, about 4% of 

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their expected total circulating blood volume. However, this sample collection is not completed at 
once, but over a 5-day period, allowing the participants to be stabilized and provide time for 
intrinsic volume replacement, including blood and plasma components. These patients usually 
receive a more extensive amount of fluid replacement therapy during their treatment. The relatively 
small negative disadvantages are outweighed by the fact that the trial seeks to better the 
understanding, and thereby the treatment of a serious, and deadly condition and the impact of 
different treatment regimens, and possible identify if there could be any risks of more severe 
complications due to treatment choice.  
 
10.1.4. Urine samples for mRNA analysis 
Urine at a volume of up to a total of 10 mL collected over three time points are collected during the 
collection of the blood samples as described in section 10.1.3 Collection of venous or arterial blood 
samples. The urine is then frozen and stored in the biobank prior to analysis.  
 
10.1.5. Non-invasive hemodynamic monitoring of patients with hypotension and 
shock 
The HemoSphere™ ClearSight™ finger cuff is a non-invasive method for measuring hemodynamic 
parameters and is not associated with any harm or side effects.52,174 These data are only collected 
from patients included at specific sites in Denmark.  
 
10.1.6. Thermography changes in early treatment of hypotension and shock 
Thermography poses no risk for patients during capture of the images, nor does the measurement of 
capillary refill time. Pictures captured consists of both normal images and thermographic images, 
including relevant file metadata. Images are stored securely and will only be accessible for the trials 
research staff. These data are only collected from patients included at specific sites in Denmark. 
 

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10.2. National regulations 
Regulations regarding ethicpal requirements and enrolment of patients are following international 
EU law and regulations including applicable national law in participating countries.1,159 European 
regulations require the trial to be authorized through the CTIS database. Data will be handled as 
described in section 9. Data collection and management.    
 
10.3. Low intervention trial 
A low-intervention trial under the EU Regulation No. 536/2014 is defined with the following 
requirements:1 
1. The investigational medicinal products, excluding placebos, are authorised;  
2. According to the protocol of the clinical trial; 
a. The investigational medicinal products are used in accordance with the terms of the 
marketing authorisation; or  
b. The use of the investigational medicinal products is evidence-based and supported 
by published scientific evidence on the safety and efficacy of those investigational 
medicinal products in any of the Member States concerned; and 
3. The additional diagnostic or monitoring procedures do not pose more than minimal 
additional risk or burden to the safety of the subjects compared to normal clinical practice in 
any Member State concerned. 
 
The trial fulfills the requirements for being defined and approved as a the low-intervention trial by 
the following considerations: 
1. Noradrenaline as an IMP is authorized in the member states and has been in routine use for 
decades. 
2. It is used in accordance with the marketing authorization other than the use of peripheral 
access as route of administration instead of central venous access. 
The choice of administration route and applicability in relation to international literature and 
evidence for this choice, including additional risk or burden to safety is thoroughly 
described in section 6. Pharmacovigilance and section 7. Safety and harm.  
 

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10.4.  Informed consent procedures 
10.4.1. Ethical review committee 
The trial will require ethical approval by the national ethical research committees as applicable by 
each member state.  
 
10.4.2. Trial-specific procedures 
As the trial is conducted as an “Clinical trial in relation to emergency situations” and as an “acute 
drug trial” in accordance with European, chapter V, article 35,1 the patient will be enrolled in the 
study when the clinical and research staff screens and finds the patient applicable for inclusion in 
accordance with the inclusion and exclusion criteria.  
The considerations for acute drug trials following the EU regulation1 are the following:  
 
1) Due to the severity of the illness and condition, the patient is not expected to be able to 
provide informed consent prior to inclusion. 
2) There is scientific evidence that enrolment and treatment in the trial will improve the 
patient’s clinical condition and health.  
3) It’s not possible to wait for informed consent from the patient or their legally appointed 
representative, due to the therapeutic initiation of the intervention being too short.  
4) The investigators attest, that they have no prior knowledge whether the person has refused to 
take part in clinical trials.  
5) That the clinical condition is critical and emergent, therefore, that the intervention can only 
be conducted in acute situations.  
6) That enrolment in the trial provides minimal risk and burden to the patient and their 
condition. 
As the patients’ critical condition eliminates the possibility to achieve informed consent within the 
timeframe of the studied intervention, and as no other patient group that can provide consent is 
possible to identify, this trial fulfils the above criteria set by the regulation. For a full explanation of 
the trial considerations in the studied patient group and how this impairs the patients ability to 
provide consent within a therapeutical timeframe, see section 10.1 Research in shock and 
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10.4.3. Screening and enrolment 
The following patients will be screened by treating physician at each site: All patients ≥18-year-old 
with signs of hypotension or shock are screened. If patients are screened and evaluated as eligible 
for enrolment, the treating physician will discuss the patients’ condition and fulfilment of the trial 
requirements for enrolment with the investigator following the rules for transfer of personal data I 
accordance with GDPR.162 The investigator is responsible for decision of fulfilment of inclusion 
and exclusion criteria and if fulfilled then randomize in accordance with the trial enrolment 
procedure. Consent is handled as mentioned in section 10.4.4. Consent for participation.  
Due to the nature of the disease process, it is necessary for the investigator to receive information 
from the treating physician about the patient in addition to oral information received by other 
healthcare personnel such as emergency medicine technicians or paramedics without prior consent 
to ensure correct screening prior to inclusion in the trial. This evaluation of possible participants 
will include their current health status including known diagnoses, medications, any decision on 
intensive care eligibility, their current home status and personal life circumstances related to their 
ability in daily living for evaluating clinical frailty score. As patients’ prior healthcare records can 
be often or rarely updated due to frequent or seldom hospital admittance, data will be evaluated 
from the most recent hospital admissions that elaborate these data. As mentioned in section 13. 
Feasibility, we expect to include every 8th patient that arrive with hypotension or shock in the 
emergency department, and therefore, it can be necessary to screen up towards 2500 patients to 
identify possible participants.  
Patients who have been screened will be noted on the trial screening log at each trial site, without 
any patient identifiable data other than time of screening, sex, age, reason for exclusion if applicable 
and if inclusion was possible or not. No other data will be collected for patients not eligible for trial 
participation. If a patient is included in the study, the unique trial identification number will be 
noted in the database and screening log.  
 
10.4.4. Consent for participation 
The trial is following the regulation for “acute drug trial”1 and treatment needs to be initiated 
immediately. It is therefore not possible to obtain consent prior to enrolment, randomization and 
treatment initiation from either the patient or their legal representative.1 
 

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After the enrolment is completed, the informed consent must be obtained as quickly as possible and 
without unnecessary delay in accordance European and national law1  
 
10.4.5. Danish procedures 
Consent is achieved through the following individuals: 
• The legal guardian: Before consent can be obtained from the patient, or supplementary to 
consent obtained from the patient or the patient’s next of kin/legal representative. 
• The patient: If not deceased before consent could be obtained. 
• Next of kin/legal representative: If consent is not possible to obtain from the patient due to 
their physical or cognitive state and critical condition or if the patient is deceased. 
If the patients’ next of kin, or the legal guardian, will not provide consent for participation in the 
trial, they will be informed that they can refuse the inclusion of the patient’s data that were collected 
during the trial.  
 
10.4.5.1. Next of kin or legal representative 
The patients next of kin or legal representative will be identified from the patient’s electronic 
medical records. These records contain information including name and contact for the patients 
closest relative. If the next of kin is attainable for consent, the consent will be obtained from the 
closest relative such as their spouse. If no spouse is available, the patients’ parents, children or 
siblings will be contacted. If none of these are registered any other registered contact will be 
contacted to obtain consent, either through them (if registered as such) or by attaining information 
on any closer relative to the patient. If no relative can be contacted and the patient survives during 
the treatment, the patient will be contacted for consent as soon as possible following the usual 
procedure of the trial. If the patient is deceased before obtaining consent, this will be obtained 
following the procedures described in section 10.4.5.4 Procedures for deceased patients. Error! 
Reference source not found.. Error! Reference source not found..  
 

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10.4.5.2. Legal guardian 
The legal guardian is a physician with no relation to the trial, but with knowledge in handling of 
acute and emergent situations in patient treatment. Prior to conduction of the trial, at least one 
physician from each Danish region with an active trial site will be identified by the Sponsor and 
informed of the trial and procedures of informed consent in emergency situations. Any questions 
and thoughts on the project will be discussed beforehand with the legal guardian and followed-up if 
any modifications to the trial are implemented. The physicians will be either an anaesthesiologist, 
intensivist or emergency physician not employed at any of the trial sites. After patient inclusion and 
randomization the legal guardian will be contacted as soon as possible and without unnecessary 
delay to obtain their consent following the procedures mentioned in section 10.4.4. Consent for 
participation. 
 
10.4.5.3. Procedures on information on the trial  
Information about the trial, inclusion and need for consent will be presented in both oral and written 
form. Information for consent will be delivered by either the principal investigator or their delegate, 
such as another investigator or sub-investigator, who is also a physician or any physician who has 
been informed, educated and have signed agreement with the principal investigator on the trial. If 
possible, the consent should be given in a room with minimal risk of disturbance during the 
conversation, to give optimal surroundings for the decision. The patient or their next of kin/legal 
representative will have any necessary and requested time to consider providing consent for 
participation. Prior to fully obtaining the consent, the investigator will ensure that the patient or 
their next of kin understand the information presented. This is usually achieved through discussion 
with the informed person and ensuring that they can reference the relevant information of the trial. 
Due to the nature of the investigated intervention, continuation of treatment will be conducted 
during this period, unless the patient or next of kin/legal representative refuses.  
Patients already included in the trial, who are not able to speak and understand Danish due to 
insufficient language skills (e.g., immigrant with no or sparse education in Danish) will receive the 
oral information with the help from a professional interpreter or from an investigator native in the 
patient’s own language. As patients will be enrolled without prior consent, it is not possible to 
translate the participant information to all possible necessary languages, thus this will only be 
available in Danish for sites in Denmark. 

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10.4.5.4. Procedures for deceased patients 
In case of death of the participant prior to consent being obtained by either the patient or next of 
kin/legal representative, the investigators will make reasonable attempts to contact the next of 
kin/legal representative of the patient. This is most likely achieved through prior registration of 
contact information in the participants electronic medical records. If no such information is 
available, the investigators will try to reach out through usual procedures for informing relatives 
and next of kin of deceased patients completed by the departments when such information is 
unavailable. If no contact at any point can be established, the participants trial data will be used in 
the trial in accordance with national law. 
 
10.4.6. Swedish procedures 
Informed consent is to be obtained from the patient and/or from the legal representative if the 
patient has a legal representative (with the authority to make healthcare decisions) registered prior 
to study inclusion. 
 
Consent is achieved through the following individuals: 
• The patient: If not deceased before consent could be obtained. 
• The legally designated representative: For consent in patients who are incapacitated and by 
that not in a state where they can provide legal consent for participation.  
 
10.4.6.1. Legally designated representatives 
The legally designated representative is a natural or legal person, authority or body which, 
according to the law is empowered to give informed consent on behalf of a subject who is an 
incapacitated subject or a minor. In the trial, if such legally designated representative exists, they 
are sought out for consent as soon as possible and without unnecessary delay after inclusion in the 
trial.  
The legally designated representative will usually be registered in the patients’ medical records and 
the research staff will reach out to them if they are not present in the department at the time of 
inclusion. If uncertain whether a patient has a legally designated representative, The Chief Guardian 

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Board (Överförmyndarnämnden) will be contacted as early as possible during their opening hours. 
The information procedures are described in section 10.4.6.2 Consent for Swedish Patient 
Participation. 
 
10.4.6.2. Consent for Swedish Patient Participation 
In Sweden, most patients with a registered legal representative are those with cognitive impairments 
(such as dementia), and since this category is often not considered for specialised intensive care 
therapy—an exclusion criterion in the study—a registered legal representative would likely be a 
rare option for obtaining informed consent. Additionally, it is important to note that in Sweden, a 
legal representative does not necessarily have the authority to make healthcare decisions unless this 
right has been specifically granted. Therefore, obtaining patient consent as soon as possible after 
inclusion would, in practical terms, most often be the only option. 
 
Informed consent should be obtained as soon as the patient's condition is stabilised, treatment of the 
underlying conditions is initiated, and the patient’s cognitive state has improved sufficiently for 
them to receive, understand, and make a decision about participating in the trial. It is anticipated 
that most patients will be able to provide informed consent within the first 24 hours. If the patient’s 
cognitive condition does not allow for informed consent within the first 24 hours (the intervention 
period), an attempt to obtain consent will be made each weekday while the patient remains 
hospitalised (in any department within the hospital). Every contact and assessment of the patient’s 
ability to consent will be documented in the medical record. The assessment of consent capacity 
will be conducted by the principal investigator or their delegate, such as another investigator or sub-
investigator who is a physician, or by any physician who has been informed, trained, and has signed 
an agreement with the principal investigator for the trial to conduct informed consent (see section 
10.4.6.3 Procedures on information on the trial) In the unlikely event that the patient is unable to 
provide consent during hospitalisation—such as if the underlying condition and shock lead to 
prolonged or chronic cognitive impairment—only data collected up until discharge and 30-day 
outcome data will be used.. If cognitive impairment persists throughout the hospitalisation, it is 
unlikely that the patient will fully recover cognitive function. However, an attempt will be made to 
contact the patient after 6 and 12 months to reattempt informed consent and enable a 12-month 
follow-up.  
 

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If the patient does not accept inclusion in the study, no more data will be registered after the time of 
this decision. Data from before this decision will still be used in the study. If the patient explicitly 
requests that no data be used in the study, then none of the patient’s data will be included. 
In the unlikely case that the patient has a registered legal representative with the authority to assist 
in healthcare decisions, this person will be contacted as soon as possible. The legal representative 
will be identified from the patient’s electronic medical records. If uncertain whether a patient has a 
legally designated representative, The Chief Guardian Board (Överförmyndarnämnden) will be 
contacted as early as possible during their opening hours. 
10.4.6.3. Procedures on information on the trial 
Information about the trial, inclusion and need for consent will be presented in both oral and written 
form. Information for consent will be delivered by either the principal investigator or their delegate, 
such as another investigator or sub-investigator, who is also a physician or any physician who has 
been informed, educated and have signed agreement with the principal investigator on the trail. If 
possible, the consent should be given in a room with minimal risk of disturbance during the 
conversation, to give optimal surroundings for the decision. The patient or legal representative will 
have any necessary and requested time to consider providing consent for participation. Prior to fully 
obtaining the consent, the investigator will ensure that the patient understand the information 
presented. This is usually achieved through discussion with the informed person and ensuring that 
they can reference the relevant information of the trial. Due to the nature of the investigated 
intervention, continuation of treatment will be conducted during this period, unless the patient/legal 
representative refuses.  
Patients already included in the trial, who are not able to speak or Swedish due to insufficient 
language skills (e.g., immigrant with no or sparse education in Swedish) will receive the oral 
information with the help from an interpreter. As patients will be enrolled without prior consent, it 
is not possible to translate the participant information to all possible necessary languages, thus this 
will only be available in Swedish for sites in Sweden. 
10.4.6.4. Procedures for deceased patients 
In the event of the participant’s death prior to consent being obtained from either the patient or the 
legal representative, the investigators will make reasonable attempts to contact the legal 
representative, if one exists. If no registered legal representative exists, the participant’s trial data 
will be used in the study. 

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10.4.7. Registration of obtained consent for participation 
The consent will be signed either in paper form and stored locally in the TMF or directly as an 
electronic signed consent form through REDCap, using a device, e.g., tablet signed by both the 
consenting individual, investigator, and the legal guardian.  
In Denmark the electronic signature can be completed either with direct signature on an electronic 
copy of the paper form. For patients included in Denmark consent can also be sought using the 
personal electronic signature validation MitID hosted by The Danish Agency for Digital 
Government.175 The touch-screen written signature for electronic signature will require same 
security validation level as required for MitID. 
In Sweden, the obtained consent will be signed on a paper form and securely stored locally at the 
trial site. 
 
 
10.4.8. Participation in sub-studies 
Participants enrolled at sites conducting any of the VASOSHOCK sub-studies will receive 
information in relation to the inclusion in the specified sub-studies that they are enrolled in. This 
information will consist of supplemental informed consent appendices describing the relevant sub-
studies if not otherwise described in the general consent form. No Swedish patients participate in 
sub-studies outside the long-term follow-up study.  
Patients enrolled in the sub-studies related to blood samples stored in the research biobank receive a 
separate informed consent form in addition to the main trials consent form. This includes both 
written and oral information on the specific studies including a separate consent form that needs to 
be signed in addition to the form in the main trial.  
 
10.5. Protection of patient data 
Patient data will be stored in compliance with the European and national laws regulations for 
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Clinical Trial Regulations.1,2,161  All data storage will be handled for at least 25 years as mandated 
by the EU regulation.1   
10.5.1. Overall procedures 
Data will be collected partly in writing, such as the paper case report form (paper-CRF) and written 
consent, and partly using the electronic CRF (eCRF). All data will be uploaded and stored in the 
eCRF using the web-based software platform REDCap hosted at Odense University Hospital via 
OPEN. All data access are logged at a person level and access is handled with individual login 
credentials and multi factor authentication. 
The database will be built to only allow personal access the relevant parts of the database, such as 
the Sponsor and GCP monitoring unit having full access. Sub-investigators will be able to access 
patients related to their own trial site and inclusion. The primary investigator and research nurse for 
each trial site will have access to the full eCRF for their own trial site, but not access to patients or 
data included from other trial sites.   
Data stored in paper form such as the paper-CRF will be stored in a secured locker at each trial site 
only accessible by the relevant trial parties.  
 
10.5.2. Specific swedish procedures 
Patients enrolled in Sweden will be allocated a unique study ID number according to the enrolment 
procedure. A patient enrolment log will include the study ID number and the Swedish identity 
number, and this file will be stored separately on a secure server with two-factor authentication, 
accessible only to the Swedish investigators. Data will be registered in the dedicated web-based 
software platform REDCap, hosted at Odense University, with reference to the study ID number. 
The Swedish identity number will not be registered or used outside Sweden. For data handled by 
any other organization, inside or outside the European Union, appropriate agreements and/or 
documentation will be established to ensure that data processing is performed in accordance with 
GDPR and other relevant legislation, before any data transfer takes place.161,162 
 
10.5.3. Measures in case of breach of data security 
If any data breach is identified, the Sponsor, by delegate the Coordinating Investigator or other 
relevant trial staff with the delegated responsibility, will handle the data breach according to the 

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European Guidelines on Personal Data Breach under Regulation 2016/679161 and applicable 
national law. This includes informing the regulatory authority with no unnecessary delay and no 
more than 72 hours after the breach has been identified, including informing any affected 
individuals.  
As soon as possible, the Sponsor and Coordinating Investigator will carry out a risk assessment and 
handling procedure in collaboration with relevant parties (such as OPEN), including decision on 
what further measure or handlings necessary to prevent further data breach or individual 
identification.  
10.5.4. Insurance 
Danish patients included in the trial, are covered by the Danish patient insurance. Patients included 
in Region Skåne, Sweden, are covered by Region Skåne's patient insurance through “Landstingens 
Ömsesidiga Försäkringsbolag”.  
10.5.5. End of trial 
When the end of trial is reached, defined by the last patients last visit, the Sponsor, or by delegation, 
the Coordinating Investigator, will notify the authorities through CTIS that the trial has ended no 
more than 15 days after the last patients’ last visit. The Sponsor is responsible for upload of the 
summary of results to CTIS as soon as possible and no later than 1 year after completion of the 
trial.1,159 If the trial is ended earlier than planned, the reason for termination of the trial will be 
described. 
 

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11. Monitoring 
11.1.  Good Clinical Practice 
Danish trial sites will be monitored by the regional Good Clinical Practice monitoring unit affiliated 
with OPEN at Odense University Hospital. Swedish study sites will be monitored by Clinical 
Studies Sweden. Prior to study commencement there will be developed a detailed monitoring plan 
in collaboration with the Good Clinical Practice Unit at the University of Southern Denmark and 
Clinical Studies Sweden.  
A statement regarding data monitoring, audit, and access to trial data is mentioned in the Sponsor 
Statement.  
 
11.2.  Independent Data Monitoring Committee (IDMC) 
As this study is a pragmatic trial it is planned as a close resemblance to regular treatment regimens 
and protocols, and other studies have showed that the use of peripheral infused vasopressor therapy 
is a safe approach, we will not be completing an interim analysis during the trial period. Therefore, 
no independent data monitoring committee will be implemented.  
 
11.3. Auditing 
Audit during the trial period will be completed if deemed necessary or of the trial is taken out for 
auditing due to random sampling of trials. The audit will be completed in collaboration with the 
GCP-unit, Odense University Hospital, but auditors will not be part of the trial nor be part of the 
monitoring team for the trial.  
GCP-enheden 
Odense University Hospital 
J.B. Winsløws Vej 19, 2. sal 
DK-5000 Odense C 

12. Timeline 
 
2023 
2024 
2025 
2026 
 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Protocol 
developme
nt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Submissio
n for CTIS 
Part 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Submissio
ns for 
CTIS Part 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creation 
of data 
dictionary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomiz
ation lists 
and 
envelopes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Education 
of site 
personnel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Start of 
trial 
 
 
 
8/12-
23 
 
 
 
 
 
 
 
 
 
 
 
GCP 
monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment 
and 
assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2023 
2024 
2025 
2026 
 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Trial 
protocol 
manuscrip
t for 
publicatio
n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data 
analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main 
manuscrip
t writing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Publicatio
n and 
presentatio
n of main 
results 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Long-term 
follow-up 
data 
collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Long-term 
follow-up 
data 
analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Long-term 
follow-up 
manuscrip
t writing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of 
Trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
31/8-
26 

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2023 
2024 
2025 
2026 
 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Publicatio
n and 
presentatio
n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12.1.1. Biobank Timeline 
 
 
2024 
2025 
2026 
2027 
2028 
2029 
2030 
2031 
Application 
for biobank 
 
 
 
 
 
 
 
 
Planning of 
blood 
sampling and 
biobank 
storage 
 
 
 
 
 
 
 
 
Collection of 
samples 
1/5-24 
 
 
 
 
 
 
 
 
Analysis of 
samples 
 
 
 
 
 
 
 
 
GCP 
monitoring of 
biobank 
 
 
 
 
 
 
 
 
Latest 
destruction of 
samples and 
biobank 
termination 
 
 
 
 
 
 
 
31/8-31 

13. Feasibility 
Previous data on relevant patients in a Scandinavian setting, have not been published. The previous 
studies on number of hypotensive patients at Odense University Hospital7 does not stratify the 
patient groups according to clinical frailty score, or if they are eligible for ICU admittance or not. In 
the same manner, the national database for intensive care70 does not register number of patients 
evaluated for ICU admittance. Therefore, we cannot say how many patients were deemed ineligible 
before the selection of the current ICU cohorts. 
The ED at OUH therefore provides a baseline representation of the possible patient population, 
considering the similarity in demography’s throughout Scandinavia.  
At the ED of OUH, more than 2,000 patients were admitted from Odense Municipality with an 
initial SBP of <100mmHg over a 3 year period.8 This is equal to two patients/day at OUH alone, 
not considering patients admitted from other municipalities, considering that OUH does receive and 
treat patients from other municipalities on Funen. Not all hypotensive patients are admitted due to 
undifferentiated shock and hypotension, but due to suspected haemorrhagic shock, upper 
gastrointestinal bleeding, obstructive shock, and other causes. Patients admitted to OUH over a 12 
year period showed 45.7% of patients were admitted due to the before mentioned conditions and 
30.8% were due to hypovolemic shock including dehydration and trauma.6 These patients might 
need other emergent interventions than treatment with vasopressor therapy and will not be included.  
To ensure generalizability of the patient population, we will include several departments in the 
study. These departments will be a mix of both urban and rural populations, as well as university 
and regional hospitals. All departments will be receiving patients with suspicion of causes for 
hypotension such as infections and sepsis and will be able to assess, diagnose and treat these 
conditions to a modern standard, including relevant paraclinical studies such as blood tests, X-rays, 
CT-scans and so forth. All hospitals will have available ICUs, if necessary for patient admittance.  
Including every 8th hypotensive patient admitted would, in Odense alone, enable the study to be 
completed within 4 years. However, we will include at least 4 sites, and expect completion within 
12 months. However, the ED at OUH provides emergency treatment to a population of more than 
300.000 inhabitants, including regional specialty treatment not available at regional hospitals. The 
patient population is therefore larger than most other trial sites expected to participate in the trial. 
Additional sites are therefore expected to participate in the trial during the intervention period, to 
further improve the possibility for completion within a shorter time frame. The current trial is 

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estimated to run over a period of 2-3 years, so slow inclusion can be improved over time and 
smaller sites with expected slower inclusion rate, will not challenge the completion of the study.  
As the study is planned as a pragmatic study, we aim to make the inclusion and completion of the 
intervention as safe and easy as possible for the sites and trial participant, so the restrictions on trial 
inclusion will most likely be due to either lack of eligible patients for inclusion or low participation 
of screening from each trial site. The latter will be sought improved by partly employing research 
nurses part time at each site, to both extract data and follow-up on patients included, while also 
improving the participation of clinical staff to screen and include relevant patients admitted to the 
department.  
 
 

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14. Publication and dissemination 
Patients participating in the study will be able to note if they wish to be informed of the study 
results after conclusion of the trial period.  
The trial will be presented national and international conferences and manuscripts consisting of at 
least one main paper and a version of the trial protocol applicable for publication in international 
scientific journals. All sub-studies will at least be sought published as manuscripts in international 
scientific journals and if possible, presented at relevant national or international conferences and 
seminars. The main manuscript will adhere to the CONSORT guidelines for reporting of 
randomized clinical trials and any other manuscripts should adhere to the applicable 
recommendations for publication on the specific type of sub-study.176 All planned results of the trial 
will be published either positive, negative, or inconclusive.  
 
14.1. Authorship 
The coordinating investigator, Lasse Paludan Bentsen, will be first author on the main papers of the 
study, the Sponsor will be last author. The rest of the participants will be given authorship 
appropriately in accordance with International Committee of Medical Journal Editors rules for 
authorship, including applicability in related sub-studies.3  Members of the steering committee and 
the site principal investigator for sites with at least one participant inclusion in the main study, and 
relevant sub-studies, will take part in the authorship. Sites including more than 25 patients will 
receive an additional authorship for the main study paper if applicable as authors. Sites with more 
than 40 inclusions can have one additional author. Secondly, for the main paper, a trial consortium 
will be co-authored, consisting of site investigators with at least 5 individual participant inclusions. 
Other authorships will be handled in accordance with overall trial participation and individuals with 
substantial contribution in other areas than direct inclusion of patients can be eligible for authorship 
if they fulfil the ICMJE requirements.   
 
 

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15. Data sharing 
There will be no prior decision on formal data sharing other than required upload of results to CTIS 
and relevant authorities. Any further data sharing, if necessary, will be made available as de-
identified data in accordance with EU, Danish regulations and national law.1,2,159,162,177 
 
 

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16. Funding 
The trial funding is granted by The PhD Fund of The Region of Southern Denmark (592,000 DKK), 
The Medicine Fund of The Danish Regions (2,676,000 DKK) and The Region of Southern 
Denmark and Region Zealands Research Fund (1,240,000 DKK).  
The funding is administered at the Research Unit of Emergency Medicine, Department of 
Emergency Medicine, Odense University Hospital, The Region of Southern Denmark. Funding will 
be used for salary support for the Coordinating Investigator and relevant research personnel, 
monitoring of the study, equipment, medications, and other operational expenses during the study 
completion. Further applications will be sent to public or private funders before and during the trial 
if necessary. None of the funding institutions or organizations, including possible pharmaceutical 
companies, will have any role in design and conduction of the study, collection, management, 
analysis, or interpretation of the data. They will have no role in preparation, review, or approval of 
manuscripts or any decision related to manuscript content and results for publication.  
 
 

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17. Tasks and responsibilities 
17.1. Sponsor-Investigator and Coordinating Investigator 
The Sponsor has overall responsibility for the trial. In close collaboration with the sponsor, the 
coordinating investigator will develop and take responsibility for the protocol including revision, 
funding, budget overview, ethical approval, trial registration, daily management, trial oversight, 
contact to Good Clinical Practice monitoring unit, assessment of overall recruitment of patients, 
education of clinical staff in relation to the trial, potential recruitment of additional sites, data 
analysis, dissemination and presentation of results. The Coordinating Investigator or Sponsor, 
where applicable, will take responsibility of contact to relevant authorities in relation to the study 
and updating the main Trial Master File.  
 
17.2. National Coordinating Investigator in Sweden 
The national coordinating investigator takes responsibility for the areas directly related to Sweden 
and works in close collaboration with the Sponsor and the Coordinating Investigator. The national 
coordinating investigator is responsible for any relation to trial sites in Sweden including daily 
management, contact to Good Clinical Practice monitor in Sweden, education of clinical staff, 
funding and protocol revision.  
 
17.3. Steering committee 
Protocol development, funding, budget overview, trial oversight, dissemination of results and if 
necessary, responsibilities of either Sponsor or Coordinating Investigator for short time periods.  
 
17.4. Project coordinator 
The project coordinator will handle necessary tasks delegated by the Sponsor and Coordinating 
Investigator in relation to the trial. The project coordinator will assist with protocol development 
and revision, funding, budget overview, ethical approval, trial registration, daily management and 
oversight, contact to the GCP unit, communication with trial sites and research staff, organization 
and management of trial documents including the trial master file, production and revision of 

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relevant standard operating procedures, organization of meetings and other administrative tasks 
related to the coordination and management of the trial. Tasks delegated to the project coordinator 
are always carried out in close collaboration with the Sponsor and Coordinating Investigator.  
 
 
17.5. Principal Investigators at each trial site 
Responsible for site-specific screening and enrolment, in collaboration with clinical staff on site, 
evaluation of eligible patients not included education and follow-up of clinical staff on trial site, 
reporting to Sponsor or Coordinating Investigator on site-specific issues or challenges, participant 
consent for data collection and follow-up data collection for the data collection in the 30-day 
follow-up part of the trial. The Principal Investigator will, in collaboration with the Coordinating 
Investigator, handle update and handling of the trial site specific part of the Trial Master File.  
 
17.6. Research staff 
Support for the principal investigator and clinical staff at the trial sites, education, and follow-up for 
clinical staff, contact to Good Clinical Practice monitoring unit, data collection, entry and 
management including patient follow-up.  
 
17.7. Clinical team 
Screening and enrolment of patients, obtaining informed consent after receiving education to do 
this, deliver of care for both intervention and control group according to the trial protocol, 
registering of data on the paper-CRF after randomization and up until end of treatment period (24 
hours).  
 
17.8. Good clinical practice unit: 
See section 11.1 Good Clinical Practice. 
 

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18. References 
1. 
Unit TEPatCotE. Regulation (EU) No 536/2014 of the European Parliament and of the 
Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 
2001/20/EC 2014. Accessed 1st March 2023. 
2. 
Committee For Human Medicinal Products. ICH Guideline for good clinical practice E6(R2).  
2016 (https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-good-clinical-practice-
e6r2-step-5_en.pdf). 
3. 
International Committee of Medical Journal E. Defining the Role of Authors and 
Contributors. 2017. 
4. 
Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol 
items for clinical trials. Ann Intern Med 2013;158(3):200-7. DOI: 10.7326/0003-4819-158-3-201302050-
00583. 
5. 
Vincent JL, De Backer D. Circulatory shock. N Engl J Med 2013;369(18):1726-34. DOI: 
10.1056/NEJMra1208943. 
6. 
Gitz Holler J, Jensen HK, Henriksen DP, et al. Etiology of Shock in the Emergency 
Department: A 12-Year Population-Based Cohort Study. Shock 2019;51(1):60-67. DOI: 
10.1097/SHK.0000000000000816. 
7. 
Pedersen PB, Henriksen DP, Brabrand M, Lassen AT. Prevalence of organ failure and 
mortality among patients in the emergency department: a population-based cohort study. BMJ Open 
2019;9(10):e032692. DOI: 10.1136/bmjopen-2019-032692. 
8. 
Holler JG, Henriksen DP, Mikkelsen S, Pedersen C, Lassen AT. Increasing incidence of 
hypotension in the emergency department; a 12 year population-based cohort study. Scand J Trauma 
Resusc Emerg Med 2016;24(1):20. DOI: 10.1186/s13049-016-0209-4. 
9. 
Holler JG, Bech CN, Henriksen DP, Mikkelsen S, Pedersen C, Lassen AT. Nontraumatic 
hypotension and shock in the emergency department and the prehospital setting, prevalence, etiology, and 
mortality: a systematic review. PLoS One 2015;10(3):e0119331. DOI: 10.1371/journal.pone.0119331. 
10. 
Finfer S, Liu B, Taylor C, et al. Resuscitation fluid use in critically ill adults: an international 
cross-sectional study in 391 intensive care units. Crit Care 2010;14(5):R185. DOI: 10.1186/cc9293. 
11. 
Jessen MK, Simonsen BY, Thomsen MH, Andersen LW, Kolsen-Petersen JA, Kirkegaard H. 
Fluid management of emergency department patients with sepsis-A survey of fluid resuscitation practices. 
Acta Anaesthesiol Scand 2022;66(10):1237-1246. DOI: 10.1111/aas.14141. 
12. 
Jessen MK, Andersen LW, Thomsen MH, et al. Twenty-four-hour fluid administration in 
emergency department patients with suspected infection: A multicenter, prospective, observational study. 
Acta Anaesthesiol Scand 2021;65(8):1122-1142. DOI: 10.1111/aas.13848. 
13. 
Lambe K, Currey J, Considine J. Frequency of vital sign assessment and clinical deterioration 
in an Australian emergency department. Australas Emerg Nurs J 2016;19(4):217-222. (In eng). DOI: 
10.1016/j.aenj.2016.09.001. 
14. 
Pinsky MR, Cecconi M, Chew MS, et al. Effective hemodynamic monitoring. Crit Care 
2022;26(1):294. DOI: 10.1186/s13054-022-04173-z. 

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15. 
Schmidt T, Bech CN, Brabrand M, Wiil UK, Lassen A. Factors related to monitoring during 
admission of acute patients. J Clin Monit Comput 2017;31(3):641-649. (In eng). DOI: 10.1007/s10877-
016-9876-y. 
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19. Appendices 
Appendix 1: CONSORT diagram draft 
 
 
 

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Appendix 2: Clinical Frailty Scale (Danish) 
 
 
 

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Appendix 3: Conflict of interests for steering committee 
All conflicts of interest forms are available in the CTIS registration. 

Appendix 5: Summary of product characteristic for 
noradrenaline 
 
 
 
6. december 2021 
 
 
 
PRODUKTRESUMÉ 
 
for 
 
Noradrenalin "Fresenius Kabi", koncentrat til infusionsvæske, opløsning 
 
 
0. 
D.SP.NR. 
32047 
 
1. 
LÆGEMIDLETS NAVN 
Noradrenalin "Fresenius Kabi" 
 
2. 
KVALITATIV OG KVANTITATIV SAMMENSÆTNING 
1 ml koncentrat til infusionsvæske, opløsning indeholder 1 mg noradrenalin base svarende 
til 2 mg noradrenalintartrat.  
 
Kompositionen pr. ampul er givet i følgende tabel:  
 
Mængden af 
koncentrat 
Mængden af 
noradrenalin base 
Mængden af 
noradrenalintartrat 
1 ml 
1 mg 
2 mg 
4 ml 
4 mg 
8 mg 
5 ml 
5 mg 
10 mg 
8 ml 
8 mg 
16 mg 
10 ml 
10 mg 
20 mg 
 
Hver ml indeholder 40 mikrogram noradrenalin base svarende til 80 mikrogram 
noradrenalintartrat, når fortyndet som anbefalet.   
 
Hjælpestof, som behandleren skal være opmærksom på: 
Dette lægemiddel indeholder 3,4 mg natrium pr. ml.  
8 ml koncentrat til infusionsvæske, opløsning indeholder 27,2 mg natrium. 

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10 ml koncentrat til infusionsvæske, opløsning indeholder 34 mg natrium.  
 
Alle hjælpestoffer er anført under pkt. 6.1. 
 
3. 
LÆGEMIDDELFORM 
Koncentrat til infusionsvæske, opløsning 
En klar farveløs til svagt gul opløsning, praktisk talt fri for synlige partikler.  
pH 3,0-4,0. 
Osmolaritet: cirka 300 mOsm/l. 
 
 
4. 
KLINISKE OPLYSNINGER 
 
4.1 
Terapeutiske indikationer 
Noradrenalin "Fresenius Kabi" er indiceret til voksne til brug som en nødforanstaltning til 
genopretning af blodtryk i tilfælde af akut hypotension. 
 
4.2 
Dosering og indgivelsesmåde 
 
Dosering 
 
Voksne 
Den endelige koncentration af infusionsopløsningen er 40 mg/liter noradrenalin base, som 
svarer til 80 mg/l noradrenalintartrat, når fortyndet som anbefalet i pkt. 6.6.  
 
Nogle klinikere kan foretrække at fortynde til andre koncentrationer. Hvis der anvendes 
andre fortyndinger end 40 mg/l, skal beregningen af infusionshastighed tjekkes 
omhyggeligt før behandlingens start.  
 
Initial infusionshastighed 
Den initiale infusionshastighed bør være mellem 10 ml/time og 20 ml/time (0,16 til 0,32 
ml/min). Dette svarer til 0,4 mg/time til 0,8 mg/time noradrenalin base (0,8 mg/time til 1,6 
mg/time noradrenalintartrat).  
Nogle klinikere kan ønske at starte med en lavere initial infusionshastighed på 5 ml/time 
(0,08 ml/min), svarende til 0,2 mg/time noradrenalin base (0,4 mg/time 
noradrenalintartrat).  
 
Dosistitrering:  
Når en infusion af noradrenalin er etableret, bør dosis titreres i trin af 0,05-0,1 µg/kg/min 
noradrenalin base i henhold til den observerede pressoreffekt. Der er stor individuel forskel 
på den dosis, der kræves for at opnå og vedligeholde normotension. Målet bør være at 
etablere et lavt normalt systolisk blodtryk (100-120 mm Hg) eller at opnå et tilstrækkeligt 
gennemsnitligt arterielt blodtryk (større end 65-80 mm Hg – afhængig af patientens 
tilstand). 
 
Tabel 1. Dosistitrering af noradrenalin infusionsvæske, opløsning  
  

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Noradrenalin infusionsvæske, opløsning 
40 mg/l (40 µg/ml) noradrenalin base 
Patientens vægt 
Dosering (µg/kg/min) 
noradrenalin base 
Dosering (mg/time) 
noradrenalin base 
Infusionshastighed 
(ml/time) 
50 kg 
0,05  
0,15  
3,75  
0,1  
0,3  
7,5  
0,25  
0,75  
18,75  
0,5  
1,5  
37,5  
1  
3  
75  
60 kg 
0,05  
0,18  
4,5  
0,1  
0,36  
9  
0,25  
0,9  
22,5  
0,5  
1,8  
45  
1 
3,6  
90 
70 kg 
0,05  
0,21  
5,25  
0,1  
0,42  
10,5  
0,25  
1,05  
26,25  
0,5  
2,1  
52,5  
1  
4,2  
105  
80 kg 
0,05  
0,24  
6  
0,1  
0,48  
12  
0,25  
1,2  
30  
0,5  
2,4  
60  
1  
4,8  
120  
90 kg 
0,05  
0,27  
6,75  
0,1  
0,54  
13,5  
0,25  
1,35  
33,75  
0,5  
2,7  
67,5  
1  
5,4  
135  
 
Behandlingens varighed og overvågning 
Noradrenalin infusionen skal fortsætte indtil tilstrækkeligt blodtryk og vævsperfusion kan 
opretholdes uden behandling. Patienten skal overvåges nøje under behandlingen med 
noradrenalin.  
Noradrenalin skal kun administreres af sundhedspersonale, som er bekendt med dets brug 
og har egnede faciliteter til tilstrækkelig overvågning af patienten.  
 
Seponering af behandling 
Noradrenalin infusionen bør gradvist nedtrappes, da pludseligt ophør af behandlingen kan 
forårsage akut hypotension.  
 
Nedsat nyre- eller leverfunktion 
Der foreligger ingen erfaringer med behandling af patienter med nedsat nyre- eller 
leverfunktion.  
 
Ældre patienter 

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Generelt skal dosis vælges med forsigtighed til en ældre patient, startende i den lave ende 
af dosisintervallet for at afspejle en større hyppighed af nedsat lever-, nyre- eller 
hjertefunktion og samtidig sygdom eller anden lægemiddelbehandling (se pkt. 4.4).  
 
Pædiatrisk population  
Sikkerheden og effekten af noradrenalin til børn og unge under 18 år er ikke klarlagt. 
Ingen data er tilgængelige.  
 
Administration 
Administrationsvej 
Til intravenøs anvendelse kun efter fortynding.  
For instruktioner om fortynding af lægemidlet før administration, se pkt. 6.6. 
Infusionen bør ske ved en kontrolleret hastighed enten ved hjælp af en sprøjtepumpe, en 
infusionspumpe eller en dråbetæller.  
 
Noradrenalin "Fresenius Kabi" bør administreres som en fortyndet opløsning og bør 
administreres via et centralt venekateter.  
Hvis det ikke er muligt at anvende et centralt venekateter, bør noradrenalin infusionen 
administreres i en stor vene, særligt en antekubital vene, for at minimere risikoen for 
iskæmisk nekrose (hud, ekstremiteter) (se pkt. 4.4. Ekstravasation).  
 
Hvis muligt skal fastgørelse af kateret undgås, eftersom blokering af 
blodgennemstrømningen omkring røret kan forårsage stase og øget lokal koncentration af 
lægemidlet.  
 
4.3 
Kontraindikationer 
• 
Overfølsomhed over for det aktive stof eller over for et eller flere af hjælpestofferne 
anført i pkt. 6.1. 
• 
Hypotension som følge af nedsat blodvolumen (hypovolæmi) (se pkt. 4.4). 
• 
Må ikke anvendes med cyclopropan og halothan bedøvelsesmidler, idet disse kan 
forårsage alvorlige hjertearytmier herunder ventrikelflimmer. Se pkt. 4.5 vedrørende 
interaktioner.  
 
4.4 
Særlige advarsler og forsigtighedsregler vedrørende brugen 
Må ikke anvendes ufortyndet.  
 
Noradrenalin er kontraindiceret hos patienter med hypotension som følge af nedsat 
blodvolumen med undtagelse som nødbehandling for at opretholde koronar og cerebral 
arterieperfusion, indtil blodvolumenerstatningsterapi kan fuldføres (se pkt. 4.3).  
 
Noradrenalin bør kun bruges sammen med egnet blodvolumenerstatning (se pkt. 4.8).  
 
Hvis noradrenalin administreres kontinuerligt for at opretholde blodtryk i fravær af 
blodvolumenerstatning, kan følgende forekomme: alvorlig perifer eller visceral 
vasokonstriktion, nedsat nyreperfusion og urinproduktion, ringe systemisk blodcirkulation 
på trods af ”normalt” blodtryk, vævshypoksi og laktisk acidose. 
Blodvolumenerstatningsterapi kan administreres før og/eller samtidig med dette 
lægemiddel. Hvis fuldblod eller blodplasma er indiceret for at øge blodvolumen, skal det 

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dog administreres separat (f.eks. hvis det gives samtidig, brug Y-slange og individuelle 
beholdere).  
 
Forlænget administration af enhver potent vasopressor kan resultere i reduceret 
plasmavolumen, som skal korrigeres kontinuerligt med egnet behandling af væske-og 
elektrolyterstatning. Hvis plasmavolumenet ikke bliver korrigeret, kan der opstå 
hypotension, når noradrenalin seponeres, eller blodtrykket kan opretholdes med risiko for 
alvorlig perifer og visceral vasokonstriktion (f.eks. nedsat nyreperfusion) med reduktion i 
blodcirkulation og vævsperfusion med efterfølgende vævshypoksi og laktisk acidose og 
mulig iskæmisk skade; gangræn i ekstremiteterne er rapporteret i sjældne tilfælde.    
 
Når noradrenalin infunderes, bør blodtrykket og flowhastigheden kontrolleres ofte for at 
undgå hypertension, som kan være associeret med bradykardi så vel som hovedpine og 
perifer iskæmi, herunder i sjældne tilfælde gangræn i ekstremiteterne. Ekstravasation kan 
forårsage lokal vævsnekrose (se nedenstående afsnit ”Ekstravasation”).  
Der skal udvises særlig forsigtighed hos patienter med koronar, mesenterial eller perifer 
vaskulær trombose, fordi noradrenalin kan øge iskæmien og udvide infarktområdet, med 
mindre den behandlende læge mener, at administration af noradrenalin er nødvendig som 
en livsreddende procedure. Tilsvarende forsigtighed skal udvises hos patienter med 
hypotension som følge af myokardieinfarkt og hos patienter med angina, særligt 
Prinzmetal’s angina variant, diabetes, hypertension eller hyperthyroidisme. 
 
Forsigtighed tilrådes hos patienter med omfattende dysfunktion af venstre ventrikel 
associeret med akut hypotension. Understøttende behandling bør initieres samtidig med 
diagnostisk evaluering. Noradrenalin bør vær forbeholdt patienter med kardiogent shock 
og refraktær hypotension, særligt til patienter uden forhøjet systemisk vaskulær resistens.   
 
Forekomst af hjerterytmeforstyrrelser under behandlingen skal medføre en dosisreduktion.  
 
Hjertearytmier kan opstå, når noradrenalin anvendes sammen med hjertesensibiliserende 
midler, og kan være mere sandsynlige hos patienter med hypoksi eller hyperkapni.  
 
Brug af pressoraminer med kloroform, enfluran eller andre halogenerede anæstetika kan 
medføre alvorlige hjertearytmier. På grund af muligheden for øget risiko for ventrikel-
flimmer, bør noradrenalin anvendes med forsigtighed til patienter, der får disse eller andre 
hjertesensibiliserende midler eller som udviser dyb hypoksi eller hyperkapni (se pkt. 4.5).  
Samtidig anvendelse med cyklopropan og halothan anæstetika er kontraindiceret (se pkt. 
4.3).  
 
Noradrenalin bør anvendes med ekstrem forsigtighed til patienter, der får 
monoaminoxidase-(MAO)-hæmmere eller inden for 14 dage efter ophør af sådan 
behandling og hos patienter, der får tricykliske antidepressiva, adrenerge-serotoninerge 
lægemidler eller linezolid, idet det kan resultere i alvorlig forlænget hypertension (se pkt. 
4.5).  
 
Der skal udvises særlig forsigtighed hos patienter med leversvigt, alvorlig renal 
dysfunktion, iskæmiske hjertesygdomme og forhøjet intrakranielt tryk. Overdoser eller 
konventionelle doser til hypersensitive personer (f.eks. hyperthyroide patienter) kan 

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forårsage alvorlig hypertension med voldsom hovedpine, fotofobi, stikkende retrosternal 
smerte, bleghed, intens svedproduktion og opkastning. Hypertension kan eventuel føre til 
akut lungeødem, arytmi eller hjertestop.  
 
Forsigtighed bør udvises ved diabetes, idet det øger niveauet af blodsukker (på grund af 
den glykogenolytiske virkning i leveren og hæmningen af insulinfrigørelse fra 
bugspytkirtlen).  
 
Ældre patienter kan især være sensitive over for virkningerne af noradrenalin, hvilket 
skyldes den større hyppighed af lever-, nyre- eller hjertedysfunktion og samtidig sygdom 
eller anden lægemiddelbehandling. 
 
Brug af noradrenalin til børn er ikke anbefalet (se pkt. 4.2 og 5.2).  
 
Noradrenalin bør kun anvendes af læger, som er familiære med de selektive indikationer 
for dets brug. 
Når det er indiceret, skal egnet blod-eller væskeerstatningsterapi sammen med brug af 
rygleje med elevation af benene iværksættes og vedligeholdes før og/eller under 
behandlingen med dette produkt. Når noradrenalin infunderes, bør blodtrykket og 
flowhastigheden tjekkes ofte for at undgå hypertension. Derfor er det ønskeligt at registrere 
blodtrykket hvert andet minut fra tidspunktet, hvor administrationen starter, og indtil det 
ønskede blodtryk er nået og derefter hvert femte minut, hvis administrationen skal 
fortsætte. Flowhastigheden skal overvåges konstant, og patienten må aldrig efterlades uden 
opsyn, imens vedkommende får noradrenalin. Hypertension kan eventuelt føre til akut 
lungeødem, arytmi eller hjertestop.  
 
Infusionen af noradrenalin bør stoppes gradvist, idet et pludseligt ophør kan medføre et 
katastrofalt blodtryksfald. 
 
Vasopressor effekten (som skyldes den adrenerge virkning på blodkarrene) kan reduceres 
ved samtidig administration af et alfablokerende middel, mens administration af et 
betablokerende middel kan resultere i en reduktion af produktets stimulerende virkning på 
hjertet og en stigning i den hypertensive effekt (via reduceret dilatering af arteriolerne), 
som følge af beta-1-adrenerg stimulering.  
 
Ekstravasation 
Infusionsstedet bør tjekkes ofte for frit flow. Der skal udvises forsigtighed for at undgå 
ekstravasation af norardrenalintartrat ind i vævet, da det kan føre til lokal nekrose på grund 
af lægemidlets vasokonstriktive effekt. Blegning langs den infunderede vene, nogle gange 
uden åbenbar ekstravasation, har været tilskrevet konstriktion af vasa vasorum med øget 
permeabilitet af venevæggen, hvilket tillader en vis lækage. I sjældne tilfælde kan dette 
udvikle sig til overfladisk nekrose (”slough”), særligt under infusion i vener i benene hos 
ældre patienter eller hos patienter, der lider af obliterativ vaskulær sygdom. Hvis blegning 
forekommer, bør det overvejes at ændre infusionsstedet med jævne mellemrum for, at 
virkningerne af den lokale vasokonstriktion kan aftage.  
 
Okklusive vaskulære sygdomme (f.eks. aterosklerose, arteriosklerose, diabetisk 
endartiritis, Buergers sygdom) er mere sandsynlige for at forekomme i de lavere 

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ekstremiteter end de øvre. Undgå derfor at anvende vener i benene hos ældre patienter eller 
hos patienter, der lider af disse sygdomme.  
 
VIGTIGT – antidot til ekstravaskulær iskæmi 
For at hindre ”slough” og nekrose i områder, hvor ekstravasation har fundet sted, bør 
området infiltreres så hurtigt som muligt med 10 ml til 15 ml saltvandsopløsning, som 
indeholder fra 5 mg til 10 mg phentolamin, et adrenergt blokeringsmiddel. En sprøjte med 
en tynd hypodermisk kanyle bør anvendes sammen med opløsningen, der infiltreres 
rigeligt over hele området, hvilket identificeres let ved dets kolde, hårde og blege 
udseende. Sympatisk blokade med phentolamin giver umiddelbare og iøjnefaldende lokale 
hyperæmiske ændringer, hvis området infiltreres inden for 12 timer. Phentolamin skal 
gives så snart som muligt efter, at ekstravasationen er blevet opdaget, og infusionen skal 
stoppes.  
 
Natrium 
Dette lægemiddel indeholder 3,4 mg natrium pr. ml, svarende til 0,17% af den WHO 
anbefalede maximale daglige indtagelse af 2 g natrium for en voksen. 
 
4.5 
Interaktion med andre lægemidler og andre former for interaktion 
 
Frarådede kombinationer 
• Flygtige halogenerede anæstetika: alvorlig ventrikulær arytmi (stigning i hjertets 
excitabilitet) (se pkt. 4.3 og 4.4) 
• Imipramin antidepressiva: paroksysmal hypertension med mulighed for arytmi 
(hæmning af sympatomimetikas indtrængen i sympatiske fibre) 
• Serotoninerg-adrenerge antidrepressiva: paroksysmal hypertension med mulighed for 
arytmi (hæmning af sympatomimetikas indtrængen i sympatiske fibre) 
• Digitalisglykosider 
• Levodopa 
• Chlorpheniraminhydrohclorid, tripelennaminhydrochlorid og desipramin: signifikant 
stigning i toksiciteten af noradrenalin.  
• Antihistaminer, idet nogle kan blokere indtaget af katekolaminer via perifert væv og 
øge toksiciteten af injiceret noradrenalin.  
 
Kombinationer, som kræver forholdsregler og tæt lægeligt tilsyn (se pkt. 4.4) 
• Ikke-selektive monoaminoxidase (MAO)-hæmmere: stigning i vasopressoreffekten af 
sympatomimetika, som almindeligvis er moderat.  
• Selektive MAO-A hæmmere: ved ekstrapolering fra non-selektive MAO-hæmmere, 
risiko for stigning i vasopressoreffekten.  
• Linezolid: ved ekstrapolering fra non-selektive MAO-hæmmere, risiko for stigning i 
vasopressoreffekten. 
 
Effekten af noradrenalin kan blive forøget af guanethidin, guanadrel, reserpin, methyldopa 
eller tricykliske antidepressiva, amfetamin, doxapram, mazindol, rauwolfia alkaloider. 
 
Forsigtighed er påkrævet, når noradrenalin anvendes sammen med alfa- og betablokkere, 
idet det kan føre til alvorlig hypertension.  
 

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Forsigtighed er påkrævet, når noradrenalin anvendes sammen med følgende lægemidler, 
idet de kan medføre øgede hjerteeffekter: thyroidhormoner, hjerteglykosider, antiarytmika.  
 
Ergotalkaloider (ergoloide mesylater, ergotamin, dihydroergotamin, ergometrin, 
methylergometrin og methylsergid) eller oxytocin kan forstærke de vasopressoriske- og 
vasokonstriktive virkninger.  
 
Samtidig administration af propofol og noradrenalin kan føre til propofol 
infusionssyndrom (PRIS).  
 
Desmopressin eller vasopressin: den antidiuretiske effekt reduceres.  
 
Lithium reducerer effekten af noradrenalin.  
 
Noradrenalin infusionsopløsninger bør ikke blandes med andre lægemidler (med 
undtagelse af de nævnte i pkt. 6.6).  
 
4.6 
Graviditet og amning 
 
Graviditet 
Noradrenalin kan nedsætte perfusion i placenta og foranledige bradykardi hos fosteret. Det 
kan også fremkalde sammentrækninger i den gravides livmoder, som kan føre til føtal 
asfyksi sent i graviditeten. Disse eventuelle risici for fosteret bør derfor vejes op imod den 
potentielle fordel for moderen.  
 
Amning 
Det vides ikke hvorvidt dette lægemiddel udskilles i modermælk. Amning er generelt ikke 
tilrådeligt ved brug af noradrenalin som nødbehandling ved akut hypotension.  
 
Fertilitet 
Ingen studier er blevet udført for at indsamle fertilitetsdata for noradrenalin.  
 
4.7 
Virkninger på evnen til at føre motorkøretøj eller betjene maskiner 
Ikke mærkning. 
Ingen information er tilgængelig. Det anbefales derfor ikke at føre motorkøretøj eller 
betjene maskiner.  
 
4.8 
Bivirkninger 
Tabel 2 lister bivirkninger, som er rapporteret efter behandling med noradrenalin. 
Størstedelen af disse data er samlet ind fra spontan rapportering. På grund af problemer 
med at beregne rapporteringshyppighed fra spontan rapportering, er hyppigheden for de 
anførte bivirkninger ”Ikke kendt” (kan ikke estimeres ud fra forhåndenværende data). 
Disse bivirkninger er anført efter faldende hyppighed indenfor hver systemorganklasse 
(SOC).  
 
Tabel 2. Bivirkninger rapporteret med noradrenalin gennem spontan rapportering 
 
Systemorganklasse 
Bivirkning 

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Psykiske forstyrrelser 
Angst, søvnløshed, konfusion, svaghed, psykotisk tilstand 
Nervesystemet 
Forbigående hovedpine, tremor 
Øjne 
Akut glaukom (meget hyppig hos patienter, der er anatomisk 
prædisponerede med lukning af den iridocorneale vinkel).  
Hjerte  
Bradykardi1, arytmi (se pkt. 4.4), ændringer i elektrokardiogram 
(EKG), takykardi, kardiogent shock, stress kardiomyopati,  
palpitationer, stigning i kontraktiliteten i hjertemusklen som følge af 
den beta-adrenerge effekt på hjertet (inotrop og kronotrop), akut 
hjerteinsufficiens  
Vaskulære sygdomme 
Hypertension (se pkt. 4.4), perifer iskæmi2 herunder gangræn i 
ekstremiteter, nedsat plasmavolumen ved langvarig brug 
Luftveje, thorax og 
mediastinum 
Dyspnø, respiratorisk insufficiens og åndedrætsbesvær 
Mave-tarm-kanalen 
Kvalme, opkastning 
Hud og subkutane væv 
Bleghed, ardannelse i huden, blålig hudfarve, hedeture eller rødmen, 
hududslæt, nældefeber eller kløe 
Nyrer og urinveje 
Urinretention 
Almene symptomer og 
reaktioner på 
administrationsstedet  
Ekstravasation, nekrose på injetionsstedet 
1Bradykardi, sandsynligvis som en refleks som følge af en stigning i blodtrykket.  
2Iskæmi, grundet potent vasokonstriktiv virkning og vævshypoksi 
 
Hypertension kan forekomme, som kan være associeret med bradykardi så vel som 
hovedpine og perifer iskæmi herunder gangræn i ekstremiteter.  
 
Kontinuerlig administration af vasopressor for at opretholde blodtryk i fravær af 
blodvolumenerstatning kan forårsage følgende symptomer (se pkt. 4.4):  
• 
Alvorlig perifer og visceral vasokonstriktion 
• 
Nedsat blodcirkulation i nyrerne 
• 
Nedsaturinproduktion 
• 
Hypoksi 
• 
Øget laktatniveau i serum  
 
Indberetning af formodede bivirkninger 
Når lægemidlet er godkendt, er indberetning af formodede bivirkninger vigtig. Det 
muliggør løbende overvågning af benefit/risk-forholdet for lægemidlet. Sundhedspersoner 
anmodes om at indberette alle formodede bivirkninger via: 
 
Lægemiddelstyrelsen 
Axel Heides Gade 1 
DK-2300 København S 
Websted: www.meldenbivirkning.dk 
 
4.9 
Overdosering 
 
Symptomer 

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Overdosering kan føre til alvorlig hypertension, refleks-bradykardi, markant stigning i 
perifer resistens og nedsat minutvolumen. Dette kan ledsages af voldsom hovedpine, 
hjerneblødning, fotofobi, retrosternale smerter, bleghed, feber, kraftig svedproduktion, 
lungeødem og opkastning.  
 
Behandling 
I tilfælde af utilsigtet overdosering, som fremgår af overdreven stigning i blodtrykket, skal 
lægemidlet seponeres, indtil patientens tilstand er stabiliseret.  
 
4.10 
Udlevering 
B 
 
 
5. 
FARMAKOLOGISKE EGENSKABER 
 
5.0 
Terapeutisk klassifikation 
ATC-kode: C 01 CA 03. Hjerteterapi, adrenerge og dopaminerge midler. 
 
5.1 
Farmakodynamiske egenskaber 
 
Virkningsmekanisme 
De vaskulære virkninger i doser, som er sædvanlige i klinisk brug, skyldes samtidig 
stimulering af alfa- og beta-adrenerge receptorer i hjertet samt i det vaskulære system. 
Bortset fra i hjertet påvirker det overvejende alfa-receptorerne.  
 
Farmakodynamisk virkning 
Dette fører til en øgning i kraften (og i fravær af vagal inhibering) og hastigheden af 
myokardiekontraktion. Perifer resistens øges og diastolisk og systolisk tryk øges. 
 
Klinisk virkning og sikkerhed  
Stigningen i blodtrykket kan forårsage en refleksreduktion i hjertefrekvensen. 
Vasokonstriktion kan føre til reduceret blodgennemstrømning i nyrer, lever, hud og 
glatmuskulatur. Lokal vasokonstriktion kan føre til hæmostase og/eller nekrose. 
 
Effekten på blodtrykket forsvinder 1-2 minutter efter ophør af infusionen.  
 
5.2 
Farmakokinetiske egenskaber 
Der findes to noradrenalin-stereoisomerer. I Noradrenalin "Fresenius Kabi" 1 mg/ml 
koncentrat til infusionsvæske, opløsning er det den biologisk aktive L-isomer, der er til 
stede. 
 
Absorption 
• 
Subkutan: ringe. 
• 
Oral: ved oral administration bliver noradrenalin hurtigt inaktiveret i 
mavetarmkanalen. 
• 
Efter intravenøs administration har noradrenalin en halveringstid i plasma på cirka 1 til 
2 minutter. 
 

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Fordeling 
• 
Noradrenalin forsvinder hurtigt fra plasma gennem en kombineret cellulær 
genoptagelse og metabolisme. Det passerer ikke let blod-hjernebarrieren. 
 
Biotransformation 
• 
Methylering ved katekol-o-methyltransferase 
• 
Deaminering ved monoaminoxidase (MAO) 
• 
Den endelige metabolit fra begge er 4-hydroxy-3-methoxymandelsyre 
• 
De mellemliggende metabolitter omfatter normetanephrin og 3,4-
dihydroxymandelsyre. 
 
Elimination 
Noradrenalin elimineres hovedsageligt som glucuronid- eller sulfatkonjugering af 
metabolitterne i urinen. Op til 16% af en intravenøs dosis bliver udskilt uændret i urinen 
med methylerede eller deaminerede metabolitter i frie eller konjugerede former.  
 
Pædiatrisk population 
Ingen data er tilgængelige om erfaring fra farmakokinetiske studier hos pædiatriske 
aldersgrupper.  
 
5.3 
Prækliniske sikkerhedsdata 
De fleste af de bivirkninger, der kan tilskrives sympatomimetika, kommer af overdrevet 
stimulering af det sympatiske nervesystem via de forskellige adrenerge receptorer.  
 
Noradrenalin kan nedsætte perfusion i placenta og inducere føtal bradykardi. Det kan også 
forårsage sammentrækninger i livmoderen og føre til føtal asfyksi sent i graviditeten. 
 
6. 
FARMACEUTISKE OPLYSNINGER 
 
6.1 
Hjælpestoffer 
Natriumchlorid  
Natriumhydroxid (til pH-justering) 
Saltsyre (til pH-justering) 
Vand til injektionsvæsker 
 
6.2 
Uforligeligheder 
Noradrenalin "Fresenius Kabi" må ikke blandes med andre lægemidler end dem, der er 
anført under pkt. 6.6. 
Infusionsopløsninger indeholdende noradrenalintartrat er rapporteret uforligelige med 
følgende stoffer: jernsalte, alkalier og oxiderende stoffer, barbiturater, chlorpheniramin, 
chlorthiazid, nitrofurantoin, novobiocin, phenytoin, natriumbicarbonat, natriumiodid, 
streptomycin, sulfadiazin, sulfafurazol.  
 
6.3 
Opbevaringstid 
2 år 
 
Holdbarhed efter åbning af ampul:  
Lægemidlet skal anvendes straks efter første åbning.  

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Holdbarhed efter fortynding: 
Kemisk og fysisk stabilitet ved brug er påvist i 24 timer ved 25 °C. Ud fra et 
mikrobiologisk synspunkt bør præparatet bruges med det samme.  
Anvendelse af andre opbevaringstider og -betingelser er på brugerens eget ansvar og bør 
ikke overstige 24 timer ved 2 til 8 °C, medmindre fortyndingen er udført under 
kontrollerede og validerede aseptiske betingelser. 
 
6.4 
Særlige opbevaringsforhold 
Må ikke opbevares ved temperaturer over 25 °C.  
Opbevar ampullen i den ydre pakning for at beskytte mod lys. 
 
Opbevaringsforhold efter fortynding af lægemidlet, se pkt. 6.3. 
 
6.5 
Emballagetyper og pakningsstørrelser 
Type I klare glasampuller indeholdende:  
1 ml koncentrat (i pakningsstørrelserne 5, 10 eller 50).  
4 ml, 5 ml, 8 ml og 10 ml koncentrat (hver i pakningsstørrelse af 5 eller 10).  
 
Ikke alle pakningsstørrelser er nødvendigvis markedsført. 
 
6.6 
Regler for destruktion og anden håndtering 
Kun til engangsbrug.  
 
Opløsningen skal visuelt inspiceres før brug. Opløsningen skal ikke anvendes, hvis den har 
en brunlig farve, eller hvis den indeholder synlige partikler.  
 
 
Fortyndingsinstruktion: 
Tilsæt enten 2 ml koncentrat til 48 ml fortyndingsvæske til administration med 
sprøjtepumpe eller tilsæt 20 ml koncentrat til 480 ml fortyndingsvæske til administration 
med dråbetæller. I begge tilfælde er den endelige koncentration af infusionsvæsken 40 
mg/liter noradrenalin base (hvilket svarer til 80 mg/liter noradrenalintartrat).  
Andre fortyndinger end 40 mg/liter noradrenalin base kan også anvendes (se pkt. 4.2).  
Hvis der anvendes andre fortyndinger end 40 mg/liter noradrenalin base, skal beregningen 
af infusionshastighed tjekkes omhyggeligt før behandlingens start.  
 
Følgende fortyndingsvæsker kan anvendes:  
Natriumchlorid 9 mg/ml (0,9% w/v) med glucose 50 mg/ml (5% w/v) infusionsvæske.  
Glucose 50 mg/ml (5% w/v) infusionsvæske.  
Natriumchlorid 9 mg/ml (0,9% w/v) infusionsvæske 
 
Ikke anvendt lægemiddel samt affald heraf skal bortskaffes i henhold til lokale 
retningslinjer. 
 
7. 
INDEHAVER AF MARKEDSFØRINGSTILLADELSEN 
Fresenius Kabi AB 
Rapsgatan 7 

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75174 Uppsala 
Sverige 
 
Repræsentant 
Fresenius Kabi 
Islands Brygge 57 
2300 København S 
 
8. 
MARKEDSFØRINGSTILLADELSESNUMMER (NUMRE) 
64365 
 
9. 
DATO FOR FØRSTE MARKEDSFØRINGSTILLADELSE 
7. juli 2021 
 
10. 
DATO FOR ÆNDRING AF TEKSTEN 
6. december 2021 
 
 

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Appendix 6: Long-term follow up study 
After completion of the trial, a long-term follow-up study will be conducted. The long-term follow-
up will include data collection from the electronic medical records and by direct telephone contact 
to the patient at 1-year after inclusion of each patient. The telephone number is registered in the 
patients’ electronic medical records, which is updated every new visit to the hospital. If the patient 
is not reachable by this, follow-up will be sought through their next of kin.  
Before follow-up is conducted, the patients electronic medical record will be evaluated, so any 
deceased patients or their next of kin are not contacted. This is due to consideration of ethical 
implications of being contacted during a mourning period and data for the trial at 1-year is not 
relevant if the participant is deceased.  
Evaluation of the primary outcome and other data such as transfer to elderly care home facility and 
need for nursing care in private home will be collected through direct contact.  
Data on number of ED contacts and Charlson Co-morbidity index is collected from the electronic 
medical records.  
 
Primary outcome 
Patient quality of life 1 year after inclusion measured by EQ-5D-5L scale evaluated by phone call to 
each participant.163,164  
• Note: The primary outcome might not be achievable in all patients, especially patients that 
are deceased at follow-up.  
Secondary outcomes 
• 1-year mortality 
• Number of ED contacts and hospital admissions within 1 year 
Tertiary outcomes 
• Charlson Co-morbidity index by 14 days and 1 year 
• Transfer to elderly care home facility within 1 year 
• Time for new need for home nursing care in private home from inclusion and up to until 1 
year after 
• Return to work at 30 days and 1 year for people with occupational position prior to inclusion