Early Versus Differed Arterial Catheterization in Critically Ill Patients With Acute Circulatory Failure: A Multicentre, Open-label, Pragmatic, Randomised, Non-inferiority Controlled Trial (EVERDAC Trial)
Phase: NA
Conditions: Acute Circulatory Failure
Sponsor: University Hospital, Tours

PROMOTOR 
 
CHRU DE TOURS 
2, boulevard Tonnellé 
37044 TOURS cedex 9 
Brief title 
EVERDAC 
IdRCB number 
2018-A01133-52 
Local study code 
DR180137 
NCT Registration number 
NCT03680963 
TITLE 
Early versus differed arterial catheterization in critically 
ill patients with acute circulatory failure. A multicentre, 
open-label, pragmatic, randomised, non-inferiority 
controlled trial (EVERDAC trial) 
Coordinating investigator 
Dr Grégoire MULLER 
Service de Médecine Intensive Réanimation, CHR 
d’Orléans 
Protocol versoin 
Version 1 2018/06/28 
Ethics Committee 
Ethics committee: Île de France V 
Registration number: 61606 CAT2 
Date: 2018/09/04 
 
 
 

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TABLE OF CONTENT 
Glossary of terms .................................................................................................................................................. 5 
Summary .................................................................................................................................................................. 7 
MAIN CORRESPONDENTS OF THE STUDY ................................................................................................... 11 
List of participating centres and principal investigators who already gave their consent for 
participation ......................................................................................................................................................... 13 
1. 
Background ................................................................................................................................................. 14 
1.1. 
IAC use and patients outcome ............................................................................................................................. 14 
1.2. 
Morbidity related to IAC ........................................................................................................................................ 15 
1.3. 
Related costs ................................................................................................................................................................ 15 
1.4. 
Alternatives to the use of IAC ............................................................................................................................... 15 
Alternatives to invasive blood pressure measurements ............................................................................ 15 
Alternatives for arterial blood gas and arterial lactate measurements and other lab tests ........ 17 
2. 
Study objectives ......................................................................................................................................... 19 
2.1. 
Primary objective ...................................................................................................................................................... 19 
2.2. 
Secondary objectives ............................................................................................................................................... 19 
2.3. 
Outcome measures ................................................................................................................................................... 20 
Primary outcome measure ..................................................................................................................................... 20 
Secondary outcome measures .............................................................................................................................. 20 
3. 
Interventions .............................................................................................................................................. 21 
3.1. 
Differences between the usual care and the non-invasive care strategies ..................................... 23 
Description of blood pressure monitoring among randomisation group ........................................... 23 
Blood sampling technique ...................................................................................................................................... 23 
Arterial blood gas parameters .............................................................................................................................. 24 
Modalities of patients’ general management .................................................................................................. 24 
4. 
Study design ................................................................................................................................................ 25 
4.1. 
Randomisation ........................................................................................................................................................... 25 
4.2. 
Study time points definitions ............................................................................................................................... 25 
4.3. 
Inclusion and non-inclusion criteria ................................................................................................................ 25 
Inclusion criteria ......................................................................................................................................................... 25 
Non-inclusion criteria ............................................................................................................................................... 26 
4.4. 
Exclusion period for subjects inclusion in another study if suitable ................................................. 26 
4.5. 
Study outline................................................................................................................................................................ 27 
4.6. 
Schedules of procedures for each enrolled patient .................................................................................... 28 
4.7. 
Measures taken to minimise or avoid bias .................................................................................................... 29 
Recruitment .................................................................................................................................................................. 29 
Randomisation ............................................................................................................................................................. 29 
Stratification ................................................................................................................................................................. 29 
Definition of safety criteria for IAC insertion in the experimental group ........................................... 29 
Choice of the primary outcome measure .......................................................................................................... 29 
4.8. 
Duration of study for each enrolled patient ................................................................................................. 30 
4.9. 
Study duration ............................................................................................................................................................ 30 
4.10. 
Rules for interrupting the study ......................................................................................................................... 30 
5. 
Significance .................................................................................................................................................. 30 
6. 
Sample size and statistical analysis .................................................................................................... 31 
6.1. 
Sample size ................................................................................................................................................................... 31 
6.2. 
Statistical analysis of clinical outcomes ......................................................................................................... 31 
General principles ...................................................................................................................................................... 31 
Baseline characteristics ........................................................................................................................................... 31 

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Groups to be compared ............................................................................................................................................ 31 
Statistical analysis of the primary outcome .................................................................................................... 32 
Statistical analysis of secondary clinical outcomes ...................................................................................... 32 
6.3. 
Statistical analysis of medico-economic outcomes ................................................................................... 33 
General principles ...................................................................................................................................................... 33 
Medico-economic objectives .................................................................................................................................. 33 
Cost study and cost-effectiveness analysis ...................................................................................................... 33 
Budget Impact Analysis ........................................................................................................................................... 35 
7. 
Feasibility ..................................................................................................................................................... 35 
7.1. 
Recruitment capacities of the participating ICUs ...................................................................................... 36 
7.2. 
Expertise of ICUs and investigators in the field of shock resuscitation ............................................ 36 
7.3. 
Centres' skills in clinical interventional research ...................................................................................... 36 
8. 
Risk/Benefit ratio...................................................................................................................................... 36 
9. 
Ethical and regulatory considerations .............................................................................................. 37 
10. 
Access rights ........................................................................................................................................... 38 
10.1. 
Access to data ............................................................................................................................................................. 38 
10.2. 
Source data .................................................................................................................................................................. 38 
10.3. 
Confidentiality of data ............................................................................................................................................ 38 
11. 
Quality Control and Insurance ......................................................................................................... 39 
11.1. 
Instructions for collecting data .......................................................................................................................... 39 
11.2. 
Monitoring of the study .......................................................................................................................................... 39 
11.3. 
Quality control ............................................................................................................................................................ 39 
11.4. 
Data management .................................................................................................................................................... 40 
11.5. 
Audit and inspection ................................................................................................................................................ 40 
12. 
Storage of documents and data concerning the study ............................................................ 40 
13. 
Rules relating to publication ............................................................................................................ 41 
13.1. 
Scientific communication ...................................................................................................................................... 41 
13.2. 
Communication of the results to patients ...................................................................................................... 42 
13.3. 
Ceding data .................................................................................................................................................................. 42 
14. 
Costs and payments ............................................................................................................................. 42 
14.1. 
Study costs .................................................................................................................................................................... 42 
14.2. 
Study payments .......................................................................................................................................................... 42 
15. 
Evaluation of security ......................................................................................................................... 42 
16. 
Committees ............................................................................................................................................. 43 
16.1. 
Scientific committee ................................................................................................................................................. 43 
16.2. 
Data Safety Monitoring Board ............................................................................................................................ 43 
17. 
Budget Evaluation ................................................................................................................................ 43 
17.1. 
Budget of the study ................................................................................................................................................... 43 
17.2. 
Compensation for participants ........................................................................................................................... 44 
18. 
Bibliography ........................................................................................................................................... 45 
19. 
APPENDIX 1 ............................................................................................................................................. 50 
20. 
APPENDIX 2 ............................................................................................................................................. 51 
 

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Glossary of terms 
AE: adverse event 
ANSM: Agence nationale de sécurité du médicament et des produits de santé 
BIA: Budget impact analysis 
BMI: body mass index 
BP: blood pressure 
CHR: centre hospitalier régional 
CHRU: centre hospitalier régional universitaire 
CIC: centre d’investigation clinique 
CNIL: Commission nationale informatique et libertés  
CPP: Comité de protection des personnes 
CRF: case report form 
CRICS: clinical research in intensive care and sepsis group 
CVC: central venous catheter 
DRG: diagnosis related groups 
ECMO: Extra-Corporeal Membrane Oxygenation 
ENCC: Échelle Nationale des Coûts à Méthodologie Commune (National health costs scale) 
FiO2: fraction of inspired oxygen 
FNHDD: French National Hospital Discharge Database 
GDPR: General Data Protection Regulation 
IAC: indwelling arterial catheter 
ICER: incremental cost-effectiveness ratio 
ICH: international conference of harmonisation 
ICU: intensive care unit 
ITT: intention to treat 
IV: intravenous 
NIBP: non invasive blood pressure 
PaO2: arterial partial pressure of oxygen 
PaCO2: arterial partial pressure of carbon dioxide 
PEEP: positive end-expiratory pressure 
RAE: related adverse event 
SAE: serious adverse event 
ScvO2: central venous oxygen saturation 

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SOFA: sequential organ failure assessment 
SpO2: blood oxygen saturation measured by pulse oximetry 
UAE: unexpected adverse effect 

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Summary 
TITLE 
Early versus differed arterial catheterization in critically ill patients 
with acute circulatory failure. A multicentre, open-label, 
pragmatic, randomised, non-inferiority controlled trial 
(EVERDAC trial) 
SPONSOR 
CHRU de TOURS 
COORDINATOR 
INVESTIGATOR 
Dr Grégoire MULLER 
Intensive care unit, Centre Hospitalier Régional Orléans 
BACKGROUND 
/ 
RATIONALE 
The use of peripheral indwelling arterial catheter (IAC) for 
haemodynamic monitoring is widespread in the intensive care unit (ICU) 
and is recommended in patients with shock. It allows continuous 
monitoring of arterial blood pressure (BP) and facilitates quick blood 
sampling for laboratory testing while avoiding repeated vascular 
punctures. 
However, despite these advantages, there is no evidence that IAC could 
improve patient’s outcome, whereas the burden of morbidity generated 
is not minor (mainly thrombosis and infectious complications). The 
preparation and insertion of an IAC also consume resources as well as 
nurse and physician time. Moreover, the presence of an IAC has been 
shown to increase the number of blood samplings ordered for laboratory 
testing, favouring anaemia and red blood cell transfusion in excess 
during the ICU-stay, and therefore exposing patients to additional risks 
while generating additional costs. No study has so far shown better 
patient-centred outcomes with the use of an IAC during ICU-stay. 
Moreover, one large, propensity score-adjusted, retrospective study even 
suggests that the use of an IAC might be associated with increased 
mortality among patients with circulatory failure receiving continuous 
intravenous vasopressors. 
There are alternatives to the use of the IAC: 1) Recent studies have 
repeatedly shown that non-invasive BP (NIBP) measurements by 
oscillometry reliably detect hypotension (mean BP<65mmHg) and 
patients responsive to cardiovascular interventions; 2) Arterial blood 
sampling (for blood gas and lactate analysis) could be avoided by analysis 
of venous blood drawn from a central venous catheter and peripheral 

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pulse oximetry readings (SpO2) (once again a widely used non-invasive 
technology). 
Accordingly, we hypothesize that patients with shock may be managed 
without any IAC. The aim of the present study is to assess whether a less 
invasive intervention (i.e., no IAC insertion until felt absolutely needed, 
according to pre-defined safety criteria) is non-inferior to usual care (i.e., 
systematic IAC insertion in the early hours of shock) in terms of mortality 
at day 28. 
PRIMARY OBJECTIVE 
The objective of the present research is a combination of a one-sided 
test of non-inferiority and a one-sided test of superiority. A stepped 
approach will be used to evaluate these hypotheses: 
a) a less invasive intervention (i.e., no IAC insertion until felt absolutely 
needed, according to consensual and predefined safety criteria) is non-
inferior to usual care (i.e., systematic IAC insertion in the early hours of 
shock) in terms of mortality at day 28 (non-inferiority margin of 5%). 
b) a less invasive intervention is not only non-inferior but also superior to 
usual care in terms of mortality 
PRIMARY OUTCOME 
All-cause mortality by 28 days after inclusion. 
STUDY DESIGN 
Multi-centre, pragmatic, randomised, controlled, open, two-parallel-
group, non-inferiority clinical trial. 
PARTICIPANTS 
Inclusion criteria : 
 
Age ≥ 18 years the day of inclusion 
 
Existence of an acute circulatory failure defined by the presence 
of the following items 1 and 2:  
1) Persisting hypotension (systolic blood pressure less than 90 
mmHg or mean arterial blood pressure less than 65 mmHg) for 
more than 15 min at ICU admission or within the following 24 
hours, OR requirement of continuous iv vasopressor treatment 
(i.e. any dose of norepinephrine / epinephrine) 
2) Presence at least one of the following signs of hypoperfusion: 
alteration of mental status; skin mottling; oliguria defined as a 
urine output < 0.5 mL/kg body weight for at least one hour; 
arterial lactate > 2 mmol/L; peripheral venous lactate > 3.2 

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mmol/L; ScvO2 <70%
 
Free express oral and informed consent of the patient or a proxy 
in case of impossibility for the patient to consent; emergency 
inclusion possible when legal representatives and patient’s 
family are not available 
 
French health insurance holder 
Non-inclusion criteria: 
 
Acute circulatory failure, as defined by items 1 and 2 in inclusion 
criteria list (cf. supra) present for more than 24 hours 
 
NIBP device fails to display a BP value, or cuff placement 
impossible 
 
Patient for whom an ECMO therapy (either veno-arterial or 
venous-venous) is already in place or is to be initiated within the 
next 6 hours 
 
Patient treated with vasopressor doses of more than 2.5 
µg/kg/min of norepinephrine tartrate plus epinephrine for at 
least 2 hours (i.e., for instance, more than 8 mg of 
norepinephrine tartrate in 50 mL at the rate of 66 mL/hour for a 
patient weighing 70 kg) (please note that in fact this dosage 
corresponds to 1.25 µg/kg/min of norepinephrine base) 
 
Severe traumatic brain injury (i.e., traumatic brain injury with a 
Glasgow coma scale score of less than 9 before sedation) 
 
Patient previously included in the trial 
 
Body mass index (BMI) above 40 kg/m2 
 
Pregnancy 
 
Brain death 
 
Moribund patient 
 
Patient known, at time of inclusion, as being under guardianship, 
tutorship or curatorship 
INTERVENTIONS 
Two distinct strategies:
1/ Control group: usual strategy of systematic IAC insertion in the early 
hours of acute circulatory failure 
 
2/ Experimental group: non-invasive strategy consisting of blood 

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pressure monitoring by non-invasive automated cuff measurements in 
patients with acute circulatory failure, and insertion of an IAC only if 
predefined severity criteria occur.  
SAMPLE SIZE  
1010 patients 
SETTINGS 
11 centres 
EXPECTED 
DURATION 
OF THE STUDY  
Expected duration of enrolment: 36 months 
Duration of the study for a participant: 90 days 
Total duration of the study: 39 months 
EXPECTED RESULTS  
We estimate the number of ICU patients presenting with shock as 
defined by our inclusion criteria as at least 25,000/year in France. More 
than 80% of them probably undergo IAC insertion during ICU care. On 
the one hand, we expect several benefits to these patients with the 
proposed, less invasive intervention: smaller amount of blood drawn for 
lab tests, less transfusion, and less IAC-related complications such as 
catheter-related infections. On the other hand, based on recent data, we 
hypothesize that hemodynamic and ventilatory parameters can be safely 
monitored without the need of IAC insertion. As a result, we expect that 
the less invasive strategy, while not affecting mortality (or marginally 
improving survival, an effect size difficult to capture with the planned 
sample size), will decrease morbidity through minimizing the burden of 
catheter-related side effects. This would translate into significant cost 
saving at the hospital and national levels. 
 

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MAIN CORRESPONDENTS OF THE STUDY 
Coordinating investigator 
Dr Grégoire Muller 
Intensive Care Unit, Centre Hospitalier Régional, 14 avenue de l’Hôpital, CS 86709 45067 Orléans CEDEX 
2, France 
Tel: 33 2 38 51 44 46 
Fax: 33 2 38 51 41 42 
E-mail: muller.gregoire.chro@gmail.com 
 
Statistician and Methodologist 
Elsa Tavernier, INSERM CIC-P 1415 – Centre Hospitalier Régional Universitaire, 2 Bd Tonnellé 37044 
Tours CEDEX 9, France 
Tel: 33 2 47 47 46 18 
Fax: 33 2 47 47 46 62 
E-mail: elsa.tavernier@univ-tours.fr 
 
Head of methodology and data management centre 
Bruno Giraudeau, INSERM CIC-P 1415 – Centre Hospitalier Régional Universitaire, 2 Bd Tonnellé 37044 
Tours CEDEX 9, France 
Tel: 33 2 47 47 46 18 
Fax: 33 2 47 47 46 62 
E-mail: bruno.giraudeau@univ-tours.fr  
 
Economists 
Dr Solène Brunet-Houdard, Unité d'Évaluation Médico-Économique (UEME), Service d'Information 
Médicale, d'Épidémiologie et d'Économie de la Santé (SIMEES), Centre Hospitalier Régional Universitaire, 
2 Bd Tonnellé 37044 Tours CEDEX 9, France 
Tel: 33 2 18 37 08 97 
E-mail: solene.brunet-houdard@chu-tours.fr 
 
Fanny Monmousseau, Unité d'Évaluation Médico-Économique (UEME), Centre Hospitalier Régional 
Universitaire, 2 Bd Tonnellé 37044 Tours CEDEX 9, France 
Tel: 33 2 18 37 08 97 

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E-mail: f.monmousseau@chu-tours.fr 
 
Representative of the sponsor  
Julien LE BONNIEC, Centre Hospitalier Régional Universitaire, 2 Bd Tonnellé 37044 Tours CEDEX 9, 
France 
Tel: 33 2 47 47 87 37 
E-mail:j.lebonniec@chu-tours.fr

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List of participating centres and principal investigators who already gave their consent for 
participation 
NAME 
SURNAME 
TOWN 
COUNTRY 
HOSPITAL 
EMAIL
TELEPHONE 
SPECIALITY 
PLANTEFEVE 
Gaëtan 
Argenteuil 
France 
CH Argenteuil 
gaetan.plantefeve@ch-argenteuil.fr 
33 1 34 23 14 45 
Intensive 
care 
VIMEUX 
 Sylvie 
Montauban 
France 
CH Montauban 
s.vimeux@ch-montauban.fr 
33 5.63.92.81.47 
Intensive 
care 
BOULAIN 
Thierry 
Orléans 
France 
CHR Orléans 
thierry.boulain@chr-orleans.fr 
33 2 38 51 44 46 
Intensive 
care 
DEQUIN 
Pierre-
François 
Tours 
France 
CHRU Tours 
pierre-francois.dequin@chu-tours.fr 
33 2 47 47 38 55 
Intensive 
care 
 SCHNELL 
 David 
Angoulême 
France 
CH Angoulême 
david.schnell@ch-angouleme.fr 
33 5 45 24 41 57 
Intensive 
care 
 BOISSIER 
 Florence 
Poitiers 
France 
CHU Poitiers 
floboissier@yahoo.fr 
33 5 49 44 44 44 
Intensive 
care 
MARTINET 
Olivier 
Saint Denis 
de La 
Réunion 
France 
CHU de La 
Réunion 
olivier.martinet@chu-reunion.fr 
33 2 62 90 56 90 
Intensive 
care 
AZAIS 
Marie-Ange 
La Roche sur 
Yon 
France 
CHD La 
Roche/Yon 
marie-ange.azais@chd-vendee.fr 
33 2 51 44 60 87 
Intensive 
care 
MEZIANI 
Ferhat 
Strasbourg 
France 
Nouvel Hôpital 
Civil (NHC) 
CHU Strasbourg 
ferhat.meziani@chru-strasbourg.fr 
33 3 88 11 67 68 
Intensive 
care 
QUENOT 
Jean-Pierre 
Dijon 
France 
CHU Dijon 
jean-pierre.quenot@chu-dijon.fr 
33 3 80 29 37 51 
Intensive 
care 
MARTIN 
Maelle 
Nantes 
France 
CHU Nantes 
maelle.martin@chu-nantes.fr 
33 2 40 08 73 65 
Intensive 
care 
 

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1. Background 
The insertion of an indwelling arterial catheter (IAC) is a common practice in intensive care units (ICU) 
patients over the world. In the United States, up to 38% of ICU patients may receive it.(1) A European 
point-prevalence study performed in 1417 ICUs showed that 44% of ICU patients underwent IAC 
insertion.(2) 
In our department in Orléans, France, 47% of the admitted patients have at least one day with an IAC. 
Ninety-four per cent (94%) of patients receiving continuous iv vasopressor therapy and 80% of patients 
placed under invasive mechanical ventilation also receive an IAC during their ICU stay. Large-scale 
multicentre data regarding the frequency of IAC use in French ICUs are lacking. However, our local 
practice seems quite close to that of other ICUs in France: In a recent multicentre observational study 
from our group that focused on volume expansion practice in patients with circulatory failure in 19 
French ICUS (including most of the 11 participating centres anticipated for the present project), we 
observed that 53% of patients were already carrying an IAC at the time they received their first fluid 
bolus in the ICU. This proportion increased parallel to the number of fluid boluses received to reach 
100% in patients receiving more than seven fluid boluses. We also observed that, on average, more than 
85% of patients who were receiving continuous iv vasopressor therapy at the time they were 
administered a fluid bolus, were carrying an IAC at the same time.(3) 
The reasons for this widespread use of IAC are that it allows continuous measurements of blood pressure, 
a key physiological variable that drives organ perfusion, and facilitates blood sampling for laboratory 
testing while avoiding several vascular punctures.(1,4,5) Therefore, despite the lack of high-level 
evidence of the benefits it could bring to ICU patients, the IAC insertion is commonly recommended to 
manage patients with septic shock or other kinds of shock.(6,7) 
1.1. IAC use and patients outcome 
Despite these supposed benefits and its widespread use, there is no evidence that an IAC could benefit 
to patients with shock through improved survival or decreased morbidity, discomfort and pain. One 
observational study even showed, while adjusting for a propensity score to receive or not an IAC, an 
increased mortality associated with IAC use among patients receiving vasopressors.(8) More recently, in 
a large cohort of ventilated patients who did not require vasopressor support, Hsu et al showed no 
difference in day-28 mortality after propensity score matching to receive or not an IAC between patients 
with and without IAC. Interestingly, when survivors were separately analysed, there were no between-
group differences in ICU and hospital length of stay.(9) The authors concluded that randomized 
controlled trials were mandatory to investigate the impact of IAC use on patients’ outcomes. 

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1.2. Morbidity related to IAC 
The use of an IAC is not free of complications. Vascular complications such as thrombosis (from 20% to 
60%),(10-12) ischemia, hematoma, pseudo aneurysm are not rare events. Infectious complications and 
bloodstream infections are also common: the incidence density is close to 11 per 1000 IAC-days for 
colonization and 1 per 1000 IAC-days for related infection.(12) 
Moreover, some authors suggest that the presence of an IAC, since it facilitates blood sampling, may 
increase the number of unnecessary blood samples drawn, therefore favouring anaemia and red blood 
cell transfusion during the ICU-stay.(9,13-15) 
In addition, one may speculate that the time needed to insert an IAC, during the first golden hours of 
resuscitation, could delay urgent treatments and procedures (therapeutic prescription such as fluid 
expansion or antibiotics, nurses work overload, transport to imagery or operating room). 
1.3. Related costs 
Studies that specifically examined the cost related to IAC use in ICU patients are lacking. However, one 
can speculate that this cost is high when considering the time and resources needed for IAC insertion (on 
average 20 min of doctor and 20 min of nurse time)(16) and maintenance, the high number of patients 
undergoing IAC insertion, the cost associated with catheter-related infections and perhaps undue lab 
tests and transfusions.(17-23) 
1.4. Alternatives to the use of IAC 
Alternatives to invasive blood pressure measurements 
Intra-arterial catheterization is considered the gold standard for BP monitoring. Indeed it provides 
accurate measurements, detects instant changes in BP and allows arterial blood sampling. Moreover, BP 
waveform analysis can, under certain conditions, give information about potential fluid 
responsiveness.(24,25) 
However, non-invasive blood pressure (NIBP) measurements through automated oscillometry and 
brachial cuff are widely used, even in shocked, unstable patients.(26) It is the first-line monitoring used 
during pre-hospital care, in the emergency department and often at intensive care unit (ICU) admission, 
before an intra-arterial catheter can be inserted in optimal conditions. 
Oscillometric devices measure the amplitude of pressure oscillations in the air-filled arm cuff during 
gradual deflation. As cuff deflates below systolic BP, blood flows through the reopening brachial artery 
and induces arterial wall oscillations that increase until the counterpressure exerted by the cuff allows 
minimal arterial wall tension and maximal arterial volume change. The cuff pressure at this point of 
maximal oscillation determines the mean BP. Notwithstanding some artefacts, oscillometric mean BP 
measurement is accurate to a few mmHg.(27) This point is of crucial importance since generally 

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intensivists pay great attention to the mean BP, as it represents the perfusion pressure of most organs, 
and mainly rely on it to track response to therapy in shocked patients.(28) 
 
As existing oscillometric devices and algorithms best operate within a certain range of cuff compliance, 
the cuff size is of paramount importance. Too large cuffs expose to underestimation of BP whereas too 
small cuffs expose to overestimation.(29) Clinicians should measure the patient’s arm circumference 
and scrupulously follow manufacturer instructions to choose the appropriate cuff size. 
 
With modern oscillometric devices, recent prospective studies have shown that mean and diastolic BP 
measurements with arm NIBP fulfilled the ISO Standard,(30-32) i.e., reported a mean bias of 5 mmHg or 
less when compared to the intra-arterial reference, even in hypotensive, unstable ICU patients receiving 
continuous iv vasopressors. Remarkably, arm NIBP detection of mean BP <65 mmHg was associated with 
a high area under the receiver operating characteristics curve (AUCROC) of 0.90-0.98.(30,31,33,34) 
Moreover, changes in arm NIBP have sufficient accuracy to provide good detection of a significant 
increase in intra-arterial mean BP, enabling identification of BP responders to urgent therapy (AUCROC of 
0.89-0.98 for a 10% mean BP increase cutoff).(33) In addition, arrhythmia did not alter the performance 
of the tested devices.(33) It should be noted however that oscillometric NIBP measurements still remain 
challenging in very obese patients, even when cuff size is optimal.(32,35) 
Clinicians sometimes place the cuff around a lower limb(26) when placement at the arm is impossible or 
contraindicated. NIBP measurements are less accurate if the cuff is placed at the ankle or the thigh 
rather than at the arm.(30) However, ankle and thigh NIBP still reliably detect hypotensive (mean BP < 
65 mmHg) and therapy-responding patients (AUCROC=0.93 and 0.96, respectively).(30) 
 
Despite these recent data on the accuracy and clinical usefulness of oscillometric BP measurements, 
staunch defenders of the invasive technique may still argue that the reported accuracy of oscillometry 
of about 5 mmHg is not sufficient and endangers patients by inducing inappropriate therapeutic 
decisions. However, it is worth reminding that invasive measurements through fluid-filled measuring 
systems like those used in all ICUs may suffer of technical imperfections such as over- or under-damping, 
or imprecise zero levelling.(36) This may well result in inaccuracy of about 5 mmHg, even in optimal 
conditions (level of pressure transducer, optimal damping coefficient of the measuring system): Invasive 
radial or femoral artery BP as displayed by ICU monitors may exhibit interval agreement widths of about 
5 mmHg for mean and diastolic BP and 10 mmHg for systolic BP when compared to high performance 
research tools.(37) More importantly, invasive BP is most often measured in the radial artery, and 
sometimes in the femoral artery. Radial and femoral mean BP values may differ by 5-10 mmHg(38) 

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because of the pulse-wave reflection phenomenon that amplifies the radial pressure(39) or conversely 
because of high dosages of vasopressor that constrict the brachial artery thereby dampening the radial 
pressure. Despite these potential discrepancies between radial and femoral pressures, clinicians often 
rely on the same pressure thresholds to manage therapy, regardless of whether the IAC is placed in 
radial or femoral artery. Moreover, current recommendations and guidelines for shock management do 
not specifically address this issue and often give a unique pressure threshold (mean BP of 65 mmHg), 
once again without differentiating radial and femoral measurements.(40) 
 
In summary, provided that cuff size is appropriately chosen, arm NIBP measurements have rather good 
accuracy to estimate intra-arterial pressure. Whether this accuracy is better or worse than with the use 
of usual invasive ICU equipment (IAC and fluid-filled systems) to estimate the true intra-arterial pressure 
value (i.e., measured with invasive high-fidelity systems) is not known. However, when compared to the 
intra-arterial reference measured with usual equipment, NIBP allows the detection of hypotension 
(mean BP<65 mmHg) and of significant (±10%) changes in mean BP. This holds true in patients with 
pronounced hypotension, high vasopressor dosages or arrhythmia. However, as the correspondence 
between intra-arterial and NIBP value is not perfect, and also because optimal thresholds may differ 
across oscillometric devices, clinicians may choose to favour sensitivity for detecting hypotension (mean 
intra-arterial BP < 65 mmHg) when interpreting NIBP values. To this end, the 70 mmHg value for NIBP 
may offer a clinically relevant compromise.(33) 
Alternatives for arterial blood gas and arterial lactate measurements and other lab 
tests 
Central venous lines allow the safe infusion of drugs potentially toxic to the peripheral veins, such as 
vasopressors and hyperosmotic solutions. For these reasons, they are often used when caring for ICU 
patients,(1,2) and their risk/benefit ratio seems to favour patients’ safety when compared to the use of 
peripheral venous lines.(41) 
Venous blood sampling through internal jugular or subclavian central venous catheters has been 
popularized after the study by Rivers et al in 2001 that suggested that the central venous oxygen 
saturation (ScvO2) could be a target for therapy in patients with septic shock.(42) 
Blood drawn from superior vena cava catheters can be used to estimate arterial blood gases and lactate 
concentration with variously appreciated accuracy but of potential clinical value.(43-46) As recently 
reported by our group in a large cohort of ICU patients with circulatory failure, the analysis of central 
venous blood combined with finger pulse-oximetry readings (SpO2) provide useful prediction of arterial 
pH, PaCO2, SaO2 and lactate concentration.(47) In short, when the estimation of arterial values from 

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central venous blood analysis predicts values within the normal range, this helps ruling out blood gas or 
lactate abnormal values with high probability. 
 
In routine practice most of blood drawings for laboratory testing are not followed by any change in 
therapy or by the application of a new procedure. In a literature review, van Walraven et al. estimated 
that 30% to 90% of these tests were not indicated.(48) Among them, arterial blood gas and lactate 
measurements were widely prescribed for reasons not fully evidence-based such as control after 
changes in ventilator settings, daily (or more frequent) check, or monitoring of the sickest patients for 
instance.(49-51) 
 
In summary, a number of arterial punctures and arterial blood drawings can be avoided by simply 
checking SpO2 and analysing central venous blood. This does not prevent prescribing arterial puncture in 
some cases, depending on the clinical situation and the clinician’s confidence. Of note, central lines may 
be safely used to sample blood for other purposes than blood gases or lactate monitoring, as safely done 
for decades in cancer/haematology patients.(52-55) 
 
 
 

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2. Study objectives  
2.1. Primary objective 
Our main hypothesis is based on the following observations: 
 
IAC insertion is time consuming and may delay urgent procedures 
 
IAC insertion is cost consuming 
 
IAC may lead to complications (infections, thrombosis) and undue blood samplings and transfusions 
 
NIBP, with an adapted cuff size, can be used safely and reliably to predict MAP < 65 mmHg 
 
NIBP can be used to track spontaneous or therapy-induced changes in MAP 
 
Central venous blood analysis combined with SpO2 offer clinically useful estimation of arterial 
lactate, arterial pH, PaO2, PaCO2 and SaO2 
 
Therefore, the question arises of whether ICU patients with circulatory failure would not be safely managed 
without the insertion of an IAC, contrary to what is currently done in common practice. 
 
The objective of the present research is a combination of a one-sided test of non-inferiority and a one-sided 
test of superiority. A stepped approach will be used to evaluate these hypotheses: 
a) a less invasive intervention (i.e., no IAC insertion until felt absolutely needed, according to consensual 
and predefined safety criteria [see below]) is non-inferior to usual care (i.e., systematic IAC insertion in the 
early hours of shock) in terms of mortality at day 28 (non-inferiority margin of 5%). 
b) a less invasive intervention is not only non-inferior but also superior to usual care in terms of mortality 
2.2. Secondary objectives 
1. To assess the non-invasive strategy as compared to the invasive usual strategy for the management 
of patients regarding vasopressor-free days at day 28, organ failure progression, fluid balance, and 
duration of mechanical ventilation support. 
2. To assess the impact of the non-invasive strategy on the number of lab tests ordered, the number of 
vascular punctures performed, the magnitude of related pain reported by the patients, the 
evolution of blood haemoglobin level, the number of red cell transfusions administered during the 
ICU stay, the number of catheter-related infections, and on the direct hospital medical costs of care. 
3. To determine the efficiency of the non-invasive strategy when compared to the recommended 
invasive strategy (ICER: ‘Cost/Life day gained at 28 days’). 
4. To evaluate the budget impact of the generalization of the non-invasive strategy (in case of 
demonstrated non inferiority) in France from the viewpoint of the French health system on a 5 
years’ time frame 
 

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2.3. Outcome measures 
Primary outcome measure  
All-cause mortality by 28 days after randomisation 
Secondary outcome measures  
 
To account for the potential bias brought by deaths occurring as the result of life-sustaining 
treatments withdrawal/withholding, as frequently encountered in ICUS, we will record such events 
from inclusion to Day 35 (i.e., until one week after the primary time point)(56) 
 
Cumulative incidence of death from inclusion through Day 90 
 
Cumulative survival free of IAC insertion, from inclusion through Day 90 
 
Number of patients who underwent IAC insertion, in both groups 
 
Evolution of daily Sequential Organ Failure Assessment (SOFA)(57) score during the first seven days 
 
Daily amount of intravenous fluid given for rapid vascular volume expansion from Day 1 to Day 7 
 
Daily fluid balance from Day 1 to Day 7 
 
Duration of mechanical ventilation 
 
Ventilator-free days from Day 1 to Day 28 (for this purpose patients dying between randomisation 
and Day 28 will be assigned a 0 value; for survivors at Day 28, all the days free of invasive 
mechanical ventilation through an endotracheal tube within the 28-day period will be taken into 
account) 
 
Proportion of patients treated by renal-replacement therapy between Day 1 and Day 28 
 
Renal replacement therapy-free days from Day 1 to Day 28 (for this purpose days without renal 
replacement therapy from Day 1 to Day 28 for survivors at Day 28, and from Day 1 to the date of 
death for patients dying before Day 28, will be taken into account) 
 
Proportion of patients treated by vasopressor between Day 1 and Day 28 
 
Vasopressor therapy-free days from Day 1 to Day 28 (for this purpose days without vasopressor 
therapy from Day 1 to Day 28 for survivors at Day 28, and from Day 1 to the date of death for 
patients dying before Day 28, will be taken into account) 
 
Mean daily blood volume drawn for lab testing during ICU stay 
 
Number of blood cultures performed during ICU stay 
 
Number of attempts at arterial puncture during ICU stay 
 
Evolution of blood haemoglobin level from Day 1 to Day 28 
 
Evolution of haematocrit from Day 1 to Day 28 
 
Number of red blood cell packs transfused from Day 1 to Day 28 
 
Number of transcutaneous arterial and venous puncture for lab tests, arterial catheter insertion and 
set up of monitor, blood drawing from the arterial catheter or other vascular line through ICU stay 
and time (min) spent by nurses and physicians (min) on these tasks during the first three days of the 

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ICU stay (in a random sample representing 10% of the total number of included patients). 
 
Number of arterial and central venous catheter insertion during ICU stay 
 
Numbers of arterial and central venous catheter-related infections during ICU stay, expressed as the 
incidence of new cases per 1000 catheter-days, including local and catheter-related bloodstream 
infections as consensually defined.(58,59) 
 
Numbers of local infections of arterial and central venous during ICU stay (number of new cases per 
1000 catheter-days). 
 
Numbers of arterial and central venous catheter-related bloodstream infections during ICU stay, 
(number of new cases per 1000 catheter-days). 
 
Number of bloodstream infections during ICU stay, catheter-related or not 
 
Duration of ICU stay 
 
Duration of hospital stay 
 
ICU mortality 
 
Hospital mortality 
 
Day-90 mortality 
 
Number of Adverse Events of special interest (Ischemia and/or necrosis of finger(s) or toe(s), 
documented bowel ischemia, occurrence or worsening of acute renal failure with need of renal 
replacement therapy, need of tracheal intubation in a patient previously not intubated, Cardiac 
arrest, nerve injury of upper limb(s), skin lesions at cuff location or at IAC insertion site, arterial 
thrombosis, hematoma, arterial pseudo aneurysm, haemorrhage at IAC insertion site either during 
IAC placement or later) 
 
Incremental Cost-Effectiveness Ratio (ICER): «Cost/Life day gained at 28 days’», from the health 
system viewpoint, between the non invasive strategy and the recommended invasive strategy: 
(CostsNIBP–CostsIAC)/(Life expectancy at D28NIBP–Life expectancy at D28IAC) 
 
Budget impact analysis of the generalization of the non-invasive strategy (in case of demonstrated 
non inferiority) in France from the viewpoint of the French health system on a 5 years’ time frame 
 
Patient-reported pain and discomfort related to the device used for BP monitoring will be assessed 
using numerical scales in both groups, once a day as soon as the patients are awakened and capable 
of correctly evaluating their pain and discomfort (cf. APPENDIX 1) 
3. Interventions 
Once included, the patient will be randomly assigned, for the 28 following days, to one of the following 
strategies:  
 
a) “usual care”: An IAC will be inserted as soon as possible (within the first four hours after randomization) 

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and will be maintained except in case of IAC futility (as defined below), suspected or proven IAC related 
infection or thrombosis (at discretion of attending physician) until day 28 or ICU discharge (whichever 
comes first). After day 28, clinicians may choose to maintain or to remove IAC. 
During the intervention period, in case of removal for accidental or other reasons than futility (i.e. IAC 
infection, IAC dysfunction, unavailability to draw blood), another IAC should be inserted during the next 
four hours (insertion site at the discretion of the attending physician). 
In case of IAC removal for other futility criteria than decision of palliative care, an IAC will be inserted within 
the four hours of new onset of circulatory failure as defined below: 
 
Presence of 
 
Persisting hypotension (systolic blood pressure less than 90 mmHg or mean arterial blood 
pressure less than 65 mmHg) for more than 4 hours 
 
OR requirement of continuous iv vasopressor treatment (i.e. noradrenaline tartrate at a 
dose ≥ 0,2 µg/kg/min or any dose of epinephrine) for more than 4 hours 
 
AND at least one of the following signs of hypoperfusion: alteration of mental status; skin mottling; 
oliguria defined as a urine output < 0.5 mL/kg body weight for at least one hour; arterial lactate > 2 
mmol/L; peripheral venous lactate > 3.2 mmol/L; ScvO2 <70% 
 
b) “non-invasive care”: No IAC insertion will be allowed during the first 28 days, excepted if predefined 
safety criteria (indicating absolute need of IAC insertion) are reached (see below): IAC will be inserted within 
the 4 hours of presence of safety criteria and patient will be managed as if he/she were part of usual care 
group until day 28 or ICU discharge. Arterial blood draw is allowed via direct arterial puncture as frequently 
as indicated. 
 
Criteria of IAC futility (one or more criteria defined futility) allowing IAC removal at physician’s discretion: 
 
The patient no longer needs significant vasopressor therapy (i.e. no longer needs norepinephrine 
tartrate at a dose ≥ 0,2 µg/kg/min or any dose of epinephrine) for more than 4 hours, and exhibits 
no sign of hypoperfusion (i.e., neither alteration of mental status, skin mottling, oliguria defined as 
a urine output < 0.5 ml/kg body weight for at least one hour, arterial lactate > 2 mmol/L, peripheral 
venous lactate > 3.2 mmol/L or ScvO2 <70%) 
 
Medical decision of palliative care 
 
Safety criteria for IAC insertion for patients initially randomized in the “no-IAC” group: 
As undisputable criteria are lacking in the medical literature, criteria were consensually determined (Delphi 
method) after collecting the opinion of the anticipated investigators (senior ICU physicians) in each centre. 
After two turns of notation, the following criteria were retained (since the median of notation fell between 
7 and 9 on a 9-point scale; extending from score 1 [“do not agree at all”] to score 9 [fully agree]) with low 

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(instead of strong) agreement between physicians (because the lower limit of notations fell below 4): 
 
 
Although the pulse oximetry monitor was working well at inclusion, it can no longer display any 
reliable SpO2 value 
 
Despite NIBP readings were available at inclusion, NIBP now consistently fails to display any reliable 
BP value 
 
Absolute need of one arterial blood gas measurement whereas 5 consecutive arterial puncture 
attempts have failed (Remember that we encourage the clinicians to preferably rely on SpO2 
readings and on arterial blood gas estimates derived from central venous blood analysis when a 
superior vena cava line is present) 
 
Need of veno-venous or veno-arterial ECMO 
 
Need of vasopressor dosages of more than 2.5 µg/kg/min of norepinephrine tartrate plus 
epinephrine for at least 2 hours (i.e., for instance, more than 8 mg of norepinephrine tartrate in 50 
mL at the rate of 66 mL/hour for a patient weighing 70 kg) 
 
Need of high risk surgery (left at the attending physician discretion) within the next 4 hours; in this 
case, the indwelling arterial catheter should be withdrawn within the 4 hours after the patient 
returns in ICU, unless one or several of the above criteria are fulfilled. 
3.1. Differences between the usual care and the non-invasive care strategies 
Description of blood pressure monitoring among randomisation group 
In the “usual care” group, BP will be monitored through the arterial line sensor connected to the usual 
monitoring device (fluid-filled system). Site of IAC insertion, insertion technique, skin antisepsis and 
catheter care will be at the discretion of the attending physician, according to local guidelines. Non-invasive 
BP monitoring is not allowed, except when IAC is considered futile (as defined above) and during IAC 
insertion or replacement. 
 
In the “non-invasive” group, automated oscillometric monitor will be used to monitor BP. The size of the 
cuff will be adapted according of the arm circumference and manufacturer recommendations. The 
dedicated indicator will be placed at the level of the artery. If deemed appropriate according to clinical 
context, the cuff may be placed at the lower limb.(30) 
 
In both groups, alarm thresholds and interval of BP measurements will be left at the discretion of the 
attending physician. 
Blood sampling technique 
In the “usual care” group, blood samples for lab tests will be drawn from the IAC, as many times as 

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necessary. Blood-drawing through the central venous catheter is forbidden, excepted for ScvO2 
measurements. 
 
In the “non-invasive” group, blood-drawing trough the central venous catheter is recommended for usual 
lab tests. To avoid interruption or bolus on specific continuous therapeutics, we strongly recommend 
infusing vasopressor agents in a dedicated line of the central venous catheter that should not be the line 
used for sampling. Regarding the monitoring of ventilation parameters and of the lactate blood level, we 
encourage the attending intensivists and investigators to rely on SpO2 (60,61) to assess oxygenation, and on 
predicted pH, PaCO2, and lactate derived from central venous blood analysis.(47) For this purpose, formula 
to derive estimates of arterial blood parameters and abacuses giving probabilities of true arterial values 
below or above given thresholds for each predicted value will be provided to the sites (APPENDIX 2). 
Arterial blood gas parameters 
We will develop a mobile application to automatically estimate arterial blood gas parameters from central 
venous parameters and SpO2 (see APPENDIX 2). As the study is not cluster randomized, the mobile app with 
the arterial blood parameters calculator will be available for all investigators regardless whether they are in 
charge of patients randomized in the “invasive” (presence of IAC) or the non-invasive group. To minimize 
this potential source of bias, we want to emphasise, and this will be clearly reminded in the mobile app, 
that central venous blood drawing will not be allowed in the “invasive” group, except for ScvO2 
measurements. 
Modalities of patients’ general management 
In both group, patients will be managed following international and national guidelines, except for the IAC 
insertion. 
 
Regarding blood sampling for lab tests, to avoid unnecessary blood spoliation in both arms, we strongly 
encourage investigators and attending intensivists to properly assess the real need of each lab test ordered. 
We discourage sampling for routine (daily or more frequent) monitoring or after changes in FiO2 or PEEP. If 
blood gas were drawn for suspicion of metabolic or respiratory disorder, only the control after therapeutic 
intervention will be allowed.  
In addition, to decrease blood spoliation during sampling through any vascular catheter (IAC for the invasive 
group, CVC for the non invasive group), we strongly suggest to apply the following procedure that may help 
minimizing the discard volume of blood withdrawn before the sampling.(62,63) 
After cleaning the catheter hub, draw off 3 mL (for sampling through IAC) or 5 mL (through CVC) of blood 
(i.e., at least 2 times the catheter’s priming volume)(64) with a syringe and waste the syringe. Draw the 
blood sample through the Vacutainer system. Be sure to sample blood from a line of the catheter not 
dedicated to continuous vasopressor therapy (to avoid bolus or discontinuous infusion). 

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For the centres using a closed system for reinfusion, they can continue to use it without discarding blood. 
4. Study design 
The projected study will be a multi-centre, pragmatic, randomised, controlled, open, two-parallel-group, 
non-inferiority clinical trial with 1:1 assignment of interventions. 
Although blinding is not possible due to the nature of the assessed intervention, the primary endpoint is 
objective (mortality at day 28). The trial will associate medical, surgical, and mixed ICUs, as well as academic 
tertiary care hospitals and community hospitals. 
We deliberately decided not to perform a cluster-randomized trial. This design is prone to the risk of 
selection bias. Moreover, there are few centres in the study, which could lead to chance imbalance. 
As the need for IAC insertion is rooted in intensivists’ mind when caring for patients in shock, there is a real 
risk that patients assigned to the non-invasive arm will frequently be switched to the invasive arm (with IAC 
insertion). To prevent this kind of contamination bias, the study scientific committee has set reasonable and 
consensual safety boundaries that will fix in which circumstances the insertion of an IAC will become an 
inescapable need (in terms of vasopressor requirement for instance [see the “3. Interventions” paragraph]). 
In the end, we opted for a classical standard individually randomised trial and worked at limiting group 
contamination. 
4.1. Randomisation 
Randomisation will be electronically centralised via a dedicated website.  
Randomisation will be stratified on centres, invasive mechanical ventilation (yes or no) and vasopressor 
dosage, namely < or ≥ 0.18 µg/kg/mn of continuous iv norepinephrine (ie. 0.36 µg/kg/mn of continuous iv 
norepinephrine tartrate) or of epinephrine or of the sum of both medications dosages at time of enrolment. 
The statistician in charge of the project will determine permutation blocks, the size of which will not be 
known by the investigators. 
4.2. Study time points definitions 
Patients will be declared enrolled in the study once consent obtained. 
Date and time of randomisation will determine the beginning of the intervention period (Study H0) 
4.3. Inclusion and non-inclusion criteria 
Inclusion criteria 
 
Age ≥ 18 years the day of inclusion 
 
Existence of an acute circulatory failure defined by the presence of the following items 1 and 2:  
1) 
Persisting hypotension (systolic blood pressure less than 90 mmHg or mean arterial blood 
pressure less than 65 mmHg) for more than 15 min at ICU admission or within the following 

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24 hours, OR requirement of continuous iv vasopressor treatment (i.e. any dose of 
norepinephrine / epinephrine) 
2) Presence at least one of the following signs of hypoperfusion: alteration of mental status; 
skin mottling; oliguria defined as a urine output < 0.5 mL/kg body weight for at least one 
hour; arterial lactate > 2 mmol/L; peripheral venous lactate > 3.2 mmol/L; ScvO2 <70% 
 
Free express oral and informed consent of the patient or a proxy in case of impossibility for the 
patient to consent; emergency inclusion possible when legal representatives and patient’s family 
are not available 
 
French health insurance holder 
Non-inclusion criteria 
 
Acute circulatory failure, as defined by items 1 and 2 in inclusion criteria list (cf. supra) present for 
more than 24 hours 
 
NIBP device fails to display a BP value, or cuff placement impossible 
 
Patient for whom an ECMO therapy (either veno-arterial or venous-venous) is already in place or is 
to be initiated within the next 6 hours 
 
Patient treated with vasopressor doses of more than 2.5 µg/kg/min of norepinephrine tartrate plus 
epinephrine for at least 2 hours (i.e., for instance, more than 8 mg of norepinephrine tartrate in 50 
mL at the rate of 66 mL/hour for a patient weighing 70 kg) (please note that in fact this dosage 
corresponds to 1.25 µg/kg/min of norepinephrine base) 
 
Severe traumatic brain injury (i.e., traumatic brain injury with a Glasgow coma scale score of less 
than 9 before sedation) 
 
Patient previously included in the trial 
 
Body mass index (BMI) above 40 kg/m2 (33,35,65) 
 
Pregnancy 
 
Brain death 
 
Moribund patient 
 
Patient known, at time of inclusion, as being under guardianship, tutorship or curatorship 
 
N.B.: Note that a patient already carrying an indwelling arterial catheter can still be randomized in the 
study provided that all the above criteria are respected. If randomised in the “noninvasive group”, the 
catheter should be removed within one hour following randomisation. 
 
4.4. Exclusion period for subjects inclusion in another study if suitable 
No exclusion period after the end of the trial participation. 
Patients will be excluded for participation in clinical trial investigating the usefulness of IAC during 
management of acute circulatory failure, but they will be authorized to participate to other studies. 

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4.5. Study outline 
 
 
 
 
 
 

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4.6. Schedules of procedures for each enrolled patient 
  
Inclusion 
Short-term follow up until D28 
or discharge from ICU 
(whichever comes first) 
Long-term 
follow up 
Study Day 1 starts once 
patient is randomized 
D1, D2, D3 
D4, D5, 
D6, D7 
D8 to D28 
D90 
Inclusion/exclusion criteria 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
Randomisation 
X 
 
 
 
 
Delayed pursuit consent if applicable 
 
X 
X 
X 
X 
Clinical assessment (heart rate, blood 
pressure, SpO2, pain assessed during 
transcutaneous vascular puncturea,e, 
fluid balanceb) 
 
X 
X 
X 
 
Catheter evaluation (IAC insertion, IAC 
removal, catheter-related infection) 
 
X 
X 
X 
 
Laboratory sampling status (blood 
volume draw, number of attempts at 
arterial puncture) 
 
X 
X 
X 
 
Therapeutic assessment (number of 
packs of red blood cells transfused) 
 
X 
X 
X 
 
Supportive therapy assessment 
(respiratory status, ventilator settingsc, 
renal replacement therapyc, vasopressor 
supportb) 
 
 
 
 
 
Census evaluation (survival status, in 
ICU, in Hospital) 
 
X 
X 
X 
X 
Specific laboratory testing for the study 
(SOFA) 
 
X 
X 
 
 
Blood haemoglobind 
 
X 
X 
X 
 
Number of arterial and venous 
punctures for lab tests, arterial catheter 
insertion and set up of monitor, blood 
drawings from arterial catheter or other 
vascular line, through ICU staye 
 
X 
X 
X 
 
Microcosting of staff time and 
equipment used for arterial and venous 
punctures for lab tests, arterial catheter 
insertion and set up of monitor, blood 
drawings from arterial catheter or other 
vascular line, through ICU staye 
 
X 
 
 
 
Adverse events/Serious adverse eventsf 
 
X 
X 
X 
X 
Query on the French National Hospital 
Discharge Database (at the end of the 
study) 
 
X 
X 
X 
 
a: assess by visual or numeric scale for patients able to communicate and by Behavioural Pain Scale(66) otherwise 
b: fluid balance will be assessed only from D1 to D7 
c: if applicable 
d: if available 
e: on a 10% random sample of study population 
f: Collection and reporting of adverse events will begin once the informed consent is signed 

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Patients’ follow-up:  
Patients will be examined for signs of shock and organ failures throughout their ICU stay, as done in routine 
practice. 
Their deceased/alive status will be recorded at ICU discharge, hospital discharge, by day 28 and by day 90 
 
Lost-to-follow-up 
The study centre personnel will make every possible effort to collect the survival status of the enrolled 
patients at day 28 and day 90 (by consulting electronic hospital records, telephone contact with family 
practitioner, or with patient him/herself or relatives). 
4.7. Measures taken to minimise or avoid bias 
Recruitment 
All patients admitted in the participating ICUs during the study period will be screened for eligibility. 
Investigators will make every effort to include all consecutive eligible patients to avoid selection bias. 
Investigators and study personal at each centre will fill in a screening-log form in which will be recorded 
included and non included eligible patients’ characteristics (age, gender, Simplified Acute Physiology score 
[SAPS II](67), cause of shock, ICU survival, cause of non inclusion if applicable) to allow assessing the 
representativeness of the study population and drawing conclusions concerning the generalizability of the 
results. 
Randomisation 
Randomisation is mandatory to minimise selection bias.  
Stratification 
Stratification on centres, invasive mechanical ventilation and vasopressor dosage at time of enrolment is 
planned to have well balanced groups concerning the general care approach (which could differs between 
centres). 
Definition of safety criteria for IAC insertion in the experimental group 
The study scientific committee has set reasonable and consensual safety boundaries that will fix in which 
circumstances the insertion of an IAC will become an inescapable need. Doing so will contribute to limiting 
group contamination which would occur if too many patients from the experimental group had an IAC. 
Choice of the primary outcome measure 
As blinding of investigators and of all ICU staff members is not technically feasible, we chose a “hard” 
endpoint (Day-28 mortality) to minimise bias. 

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4.8. Duration of study for each enrolled patient 
Patients will be declared included in the study at the time of consent. The intervention period will last 28 
days after inclusion. Patients will be followed daily until ICU discharge, until Day 28 for the primary outcome 
measure (Day 28 mortality), and until Day 90 for mortality (secondary outcome).  
The period of follow-up will be extended as needed in case of not resolved serious adverse event. 
4.9. Study duration 
Duration of the inclusion period: 36 months (given the recruiting capabilities of the participating ICUs) 
Duration of each patient’s participation: 3 months 
Total duration of the study: 39 months 
4.10. Rules for interrupting the study 
In accordance with the Declaration of Helsinki, patients have the right to withdraw from the study at any 
time for any reason. The Investigator and Sponsor also have the right to withdraw participants from the 
study. Patients may be removed from the study for the following reasons: (i) Withdrawal of consent: When 
a subject withdraws consent before completing the study, the reason for withdrawal of consent is to be 
documented on the CRF and in source documents. (ii) At the request of the Investigator or Sponsor, 
whether for administrative or other reasons. In case of adverse event, the specific event and any related 
test and visit will be recorded on the CRF and the intervention may be stopped if judged necessary for 
safety reasons. In this instance, the patient will be kept for analysis according to the intention-to-treat 
principle. 
When a subject is removed from the study, all observations collected up to the time of termination will be 
recorded on the CRF along with the reason for termination, and scheduled safety evaluations and Day 28 
follow-up examinations will be conducted, if possible. However, in case of pursuit-consent refusal, the data 
collected will not be used for statistical analysis and the patient will not be included in the final intention-
to-treat analysis. 
5. Significance 
We estimate the number of ICU patients presenting with shock as defined in our inclusion criteria as at 
least 25,000/year in France. More than 80% of them probably undergo IAC insertion during ICU stay. On the 
one hand, we expect several benefits to these patients with the proposed, less invasive intervention: 
smaller amount of blood drawn for lab tests, less transfusion, and less IAC-related complications such as 
catheter-related infections. On the other hand, based on recent data, we hypothesize that hemodynamic 
and ventilatory parameters can be safely monitored without IAC insertion. As a result, we expect that the 
less invasive strategy, while not affecting mortality (or marginally improving survival, an effect size difficult 
to capture with the planned sample size), will decrease morbidity through minimizing the burden of 
catheter-related side effects. This would translate into significant cost savings at hospital and national 

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levels. 
6. Sample size and statistical analysis 
6.1. Sample size 
In a non-inferiority randomised clinical trial, we usually hypothesize a priori an equal incidence of the event 
of interest in the two groups compared. In the present study, our a priori hypothesis is different. Indeed, we 
expect a marginal benefit of the non-invasive approach, because the systematic IAC insertion may harm the 
patients through catheter-related infections and through blood spoliation. However, even demonstrating 
that the non-invasive approach is not inferior to the systematic IAC insertion approach could be considered 
as a positive result (cf., Risk/benefit ratio section). 
We therefore assume that the mortality rate at day 28 will be 22.5% in experimental group and 25% in the 
control group. We set the non-inferiority margin at 5%, power at 80% and alpha risk at 5%. Such hypotheses 
led us to plan the inclusion of 1010 patients. 
6.2. Statistical analysis of clinical outcomes 
General principles 
The statistical analyses will be performed by the INSERM CIC 1415 unit and supervised by Elsa Tavernier. SAS 
9.4 and R 3.3 (or further versions) softwares will be used. A detailed analysis plan will be a priori defined. 
Later modifications must occur before unblinding the database. The statistical analysis will be conducted on 
the per-protocol and intention to treat (ITT) populations as recommended for non inferiority trials. A 
statistical report will be written in agreement with the standards as specified in the CONSORT Statement 
and its extension for non pharmacological interventions and for non inferiority trials (http://www.consort-
statement.org/) 
Baseline characteristics 
Baseline characteristics will be reported per group using descriptive statistics. No statistical test will be 
performed. 
Groups to be compared 
The ITT principle will be applied. Nevertheless, patients who would withdrew consent to study participation 
will be discarded, as required by the French legislation. 
Because patients are ICU patients, it is expected to have no lost-to-follow-up patient. We moreover plan to 
collect the place of birth, such that we will be able to collect the vital status asking to the city halls. If there 
are several lost-to follow-up patients, we will use multiple imputation. 
The per protocol population will be defined during the blind review. 

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Statistical analysis of the primary outcome 
The between-group difference (experimental group minus usual care group) in rates of day-28 mortality will 
be estimated based on the 2-sided 95% Confidence Interval (CI). The upper boundary of the 95% CI will be 
compared with the non inferiority margin of 5%. If non-inferiority is demonstrated, the upper bound of the 
95%CI will be compared to 0: if it is lower than 0, then a superiority conclusion will be drawn.(68) 
As a sensitivity analysis, we will perform a multivariate logistic regression, to estimate the odds ratio 
adjusted on the stratification variables.(69)  
Statistical analysis of secondary clinical outcomes 
• 
Day-90 mortality: the between-group difference in rates of day-90 mortality will be estimated based 
on the 2-sided 95% CI.  
• 
Number of patients who underwent IAC insertion, in both groups. 
No statistical test will be performed for this outcome, which would be nonsense. 
In the usual care group, the proportion of patients who underwent IAC is a measure of adherence. In the 
experimental group, the proportion of patients who underwent IAC is of relevance as it reflects the limits of 
the non-invasive approach. 
• 
The effect of intervention on changes over time of the SOFA score, the blood haemoglobin level, 
haematocrit, mean daily blood volume drawn for lab testing, mean daily amount of intravenous 
fluids given for rapid vascular volume expansion, mean daily fluid balance, daily maximum pain and 
associated 95%CI will be estimated using mixed linear models, after data transformation if 
necessary.  
• 
Duration of mechanical ventilation will be analysed using a competing risk approach, with death as 
competing risk. 
• 
The effect of intervention on proportion of patients treated by renal-replacement therapy or by 
vasopressor, proportions of patients with arterial and central venous catheter-related infections or 
bloodstream infections and associated 95%CI will be estimated using the competing risk approach, 
with death as competing risk.  
• 
The effect of intervention on number of blood cultures performed, number of attempts at arterial 
puncture, number of red blood cell packs transfused, number of arterial and central venous 
catheter insertion and associated 95%CI will be estimated using negative binomial models with 
duration of ICU stays as offset variable. 
• 
Two-sided 95% CIs of median differences of free-days (Ventilator-free days, renal replacement 
therapy-free days, vasopressor therapy-free days) will be estimated.  
• 
Duration of ICU and hospital stay: 2-sided 95% CIs of median differences will be estimated. 

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• 
The effect of intervention on ICU and hospital mortality and 95% CI will be estimated using 
competing-risk model with ICU and hospital discharge alive as competing events with death during 
the stay. 
6.3. Statistical analysis of medico-economic outcomes 
General principles 
Cost-effectiveness analyses will be performed by the Medico-Economic Evaluation Unit of Tours University 
Hospital and supervised by Solène Brunet-Houdard. They will be based on the effectiveness results obtained 
by the INSERM CIC 1415 and follow standard recommendations for health-economic analyses (HAS). 
Medico-economic objectives 
Medico-economic evaluation comprises three secondary objectives: 
• 
To assess the impact of the non-invasive strategy on the direct hospital medical costs of care 
• 
To determine the efficiency of the non-invasive strategy when compared to the recommended 
invasive strategy (ICER: ‘Cost/Life day gained at 28 days’) 
• 
To evaluate the budget impact of the generalization of the non-invasive strategy (in case of 
demonstrated non inferiority) in France from the viewpoint of the French health system on a 5 
years’ time frame 
Therefore, medico-economic criteria are: 
• 
Nurse and physician time (min) spent for arterial and venous puncture for lab tests, arterial catheter 
insertion and set up of monitor, blood drawings from arterial catheter or other vascular line through 
ICU stay (in a random sample representing 10% of the total number of included patients) 
• 
Incremental Cost-Effectiveness Ratio (ICER): «Cost/Life day gained at 28 days’», from the health 
system viewpoint, between the non invasive strategy and the recommended invasive strategy: 
(CostsNIBP–CostsIAC)/(Life expectancy at D28NIBP–Life expectancy at D28IAC) 
• 
Budget impact analysis (BIA) of the generalization of the non-invasive strategy (in case of 
demonstrated non inferiority) in France from the viewpoint of the French health system on a 5 
years’ time frame 
Cost study and cost-effectiveness analysis 
The cost-effectiveness study will last 28 days and will take into account two viewpoints (Health insurance 
and hospital). The ITT principle will be applied. 
Only the direct medical costs related to the hospitalization will be retained. Indeed, patients will be treated 
almost exclusively in hospitals during this time horizon. The direct link between one hospitalization and the 
strategy will be checked. Consumed resources will be collected during and at the end of the study: 

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1) A microcosting will be performed to count and time resources used in ICU for some specific steps 
from randomisation through day 28: 
a. preparation and insertion of an IAC and set up of monitor 
b. NIBP measurement by oscillometry 
c. arterial and venous blood sampling 
d. peripheral pulse oximetry readings (SpO2) 
e. transfusion (number of packed red blood cell transfused) 
f. dressing changes 
Staff resources (physician, nurse…) will be reported and timed separately. The equipment used for these 
steps will also be collected. The microcosting will be carried out in each centre on a sample of randomly 
selected patients (10%) and data will be collected in the Case report Form (CRF). Data from microcosting will 
allow us to present the results from the health institutions viewpoint. 
2) A query of the hospital databases (FNHDD) will take place at the end of the study to collect actual 
billing data for health insurance (DRG and supplements). This step will include all patients stay data 
from randomisation to day 28. The coding practices for DRG will be evaluated to take into account 
the heterogeneity of each centre. A specific attention will be paid to comorbidity (associated 
diagnosis) that can affect the grouping function and possibly modify the DRG. The hospitalization 
data, and particularly the activity data, will be analysed to compare patterns of patient’s care and 
comorbidity. Because of the continuous evolution of the DRG classification, hospital stays will be 
reallocated in the latest classification to keep consistency of data. Data from hospital databases will 
be used to present results from the health insurance viewpoint. 
 
The valuation of consumed resources during hospitalization will be done from the FNHDD, the national 
health costs scale (ENCC), public wage grid and public prices of resources measured by microcosting.  
Discounting will be applied to costs from the ENCC data to bring them forward to the current year. 
 
Nurse and physician time (min) spent for arterial puncture, arterial catheter insertion and set up of monitor 
will be compared between both groups. 
 
The overall costs will be computed by multiplying the numbered resources (from the economic data 
collection) by their respective costs (from the medical service valuation). 
Firstly, economic data will be used to describe the population (descriptive analysis). A comparison of 
economic data (DRG and new hospitalisations) from both groups will be carried out. 
 

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The ICER «Cost/ Life day gained at 28 days’» was chosen to rely on the primary judgment criterion. As usual, 
it will be evaluated on the same timeframe for costs and effectiveness. It will be computed and presented in 
a cost-effectiveness plan. 
 
A cost-effectiveness acceptability curve will be drawn from a bootstrap simulation to show the probability 
that the studied strategy is cost-effective for a ceiling ratio. This ratio is determined as the maximum cost 
that decision makers are willing to pay for one gained life day at 28 days. 
 
According to the “HAS” guide for economic evaluation, sensitivity analysis will be led to evaluate the 
sturdiness of the results. It will allow us to take into account the uncertainty of surrounding various 
parameters of the evaluation. The variables challenged in the sensitivity analysis will be costs and results 
(especially the nursing and physician time and the equipment used). 
The uncertainty of the ICER will be assessed using one-way deterministic sensitivity analyses (use of 
Tornado diagram to present the results). 
Budget Impact Analysis 
Only if the non-inferiority of the non-invasive strategy is demonstrated, the BIA will determine the financial 
impact (potential savings) of the wider use of the non-invasive strategy for all eligible patients in France. The 
budget impact will be analysed from the viewpoint of the health system (Hospital and Health Insurance) 
over a 5-years’ time frame. No discounting will be applied to the BIA data, in accordance with HAS 
recommendations. 
The BIA will consist in multiplying the average annual cost per patient over 5 years by the number of eligible 
patients, taking into account a penetration rate. We will estimate the financial impact of the non-invasive 
strategy considering the current and future target populations (such data will be collected from the 
literature and expert opinions). 
 
Excel®, SAS 9.4, STATA 15 and TreeAge Pro® softwares will be used for all medico-economic analyses. 
7. Feasibility 
The feasibility of the proposed study is based on (i) the ability of involved ICUs and investigators to recruit 
patients, (ii) their expertise in the field of shock resuscitation, (iii) their experience regarding inclusion in and 
conduct of interventional studies in the field of resuscitation, (iv) logistical support provided by the CRICS 
group and (v) the involvement of the CIC and the UEME-CHU Tours for the methodological, statistical 
expertise, and database management. 

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7.1. Recruitment capacities of the participating ICUs 
Overall, the 11 involved ICUs admit over 9000 patients a year (http://www.crics.fr/), and we estimate that 
patients with shock represent 15-20% of these admissions. This yields a minimum of 4050 to 5400 
potentially eligible patients over 3 years, among which 19-25% will have to be enrolled to reach the 
predetermined sample size. On average, each participating ICU will admit 10-14 potentially eligible patients 
per month. Therefore, the required mean inclusion rate of 2.6 patients/month in each centre appears 
realistic. 
7.2. Expertise of ICUs and investigators in the field of shock resuscitation 
A number of recent publications of the investigators are in the field of shock management. 
7.3. Centres' skills in clinical interventional research  
All the participating ICUs are members of the Clinical Research in Intensive Care and Sepsis (CRICS) group. 
CRICS is a group of ICUs of which the objective is to develop and professionalise clinical research in critically 
ill patients (http://www.crics.fr/). CRICS group and his partners have participated in numerous 
pharmaceutical and academic trials, and have demonstrated their ability to meet their commitments in 
terms of recruitment.  
8. Risk/Benefit ratio 
Patients included in this study are very sick patients who are exposed to numerous complications and risks 
independent of the study arm. 
Excepted for the use of an IAC, patients’ care will be managed as usual in both arms, according to national 
and international guidelines and to local operational standard procedures. Whether the risk/benefit 
balance is favourable in one arm compared to the other is in fact the very question addressed in this study. 
Every effort will be made by investigators and caregivers to minimise risks in both arms. However, our main 
hypothesis based on published data is that the systematic IAC insertion may harm the patients through 
catheter-related infections and through blood spoliation, whereas positive impact on patient-centred 
outcomes has never been documented. Hence, by minimising IAC-related morbidity, the interventional, 
less invasive strategy (no systematic IAC) might well also result in a slight but positive effect on survival. As 
this positive effect is expected to be marginal and might be difficult to capture in a study of reasonable 
sample size, we chose to design the study as a non-inferiority trial with the mortality as the primary 
outcome measure, and secondarily test for superiority if non inferiority is demonstrated. Secondary 
outcome measures will aim at assessing the IAC-related morbidity and costs.  
The scientific committee decided to present the study as a study that brings minimal risk (in the meaning of 

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the French Law)a,b to patients and a possible benefit in the intervention arm as compared to usual care, 
resulting in a potentially favourable risk/benefit balance. 
9. Ethical and regulatory considerations 
The study will be conducted in accordance with legal and regulatory requirements, as well as the general 
principles set forth in the International Ethical Guidelines for Research Involving Human Subjects. 
The study will be conducted in accordance with the present protocol. With the exclusion of emergency 
situations necessitating taking specific therapeutic actions, the investigator or investigators undertake to 
observe the protocol in all respects, in particular as regards obtaining consent and the notification and 
follow-up of serious adverse events. 
The study protocol will be submitted to the Ethics Committee (Comité de Protection des Personnes). Data 
recorded in this study will be participant to computer processing by INSERM CIC-P 1415 – University 
Hospital Centre of Tours, and these data collected during the trial will be processed in accordance with the 
requirements of the CNIL (within the framework of the Reference methodology (MR-001) and the General 
Data Protection Regulation (2016/679- GDPR)). 
 
We intend to present the study as a study exposing enrolled patients to minimal risks and possibly resulting 
in a favourable benefit/risk ratio for at least one group of patients. If such benefit/risk ratio and study 
qualification are approved by the CPP, the study protocol will be transmitted to the ANSM for information. 
Furthermore, if the CPP recognises that the study exposes the patients to minimal risks, we will ask, as 
allowed by the French Law, to have the possibility to include the patients without prior consent if patient is 
not able to consent and if relatives or legal representatives are not present. Thereafter, information will be 
given to the patient and he/she will be asked to give a delayed pursuit-consent if he/she has regained 
sufficient capacities. 
CHRU de Tours, the sponsor of this study, will take out an insurance policy covering third party liability as 
required by the French Law.  
In accordance to the French Law, this research will be registered in the European EudraCT database or in 
the ANSM “Recherches et collections biologiques (RCB)” registry depending on the qualification the CPP 
gives to the research. 
This research will be registered on the web site http://clinicaltrials.gov/ before the inclusion of the first 
patient. 
                                                 
a Loi n° 2012-300 du 5 mars 2012 relative aux recherches impliquant la personne humaine (1) (JORF n°0056 du 6 mars 2012 page 
4138) 
b Arrêté du 3 mai 2017 fixant la liste des recherches mentionnées au 2° de l'article L. 1121-1 du code de la santé publique (JORF 
n°0107 du 6 mai 2017 texte n°30) 
Règlement (UE) 2016/679 ( RGPD), 
 

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Any substantial modification, i.e. any modification of a nature likely to have a significant impact on the 
safety of the people involved, the conditions of validity and the results of the study, on the quality and 
safety of the studied strategies, on interpretation of the scientific documents which provide support for the 
study or the methods for conducting it, is the subject of a written amendment to be submitted to the 
sponsor; prior to implementing it, the latter must obtain approval from the ethics committee. 
Non-substantial modifications, i.e. those not having a significant impact on any aspect of the study 
whatsoever, are communicated to the ethics committee for information purposes. 
Any amendments to the protocol must be made known to all the investigators participating in the study. 
The investigators undertake to comply with the contents. 
Any amendment modifying the management of patients or the benefits, risks or constraints of the study is 
the subject of a new Patient Information and Informed Consent form which must be completed and 
collected according to the same procedure as used for the previous one. 
10. Access rights 
10.1. Access to data 
The sponsor is responsible for obtaining the agreement of all the parties involved in the study in order to 
guarantee direct access in all the sites where the study is being conducted to source data, source 
documents and reports, so that he can control their quality and audit them. 
The investigators will make available to the people with a right of access to these documents under the 
legislative and regulatory provisions in force (articles L.1121-3 and R.5121-13 of the French Public Health 
Act) the documents and individual data strictly necessary for monitoring, carrying out quality control and 
auditing the research. 
The Promoter, through its data protection officer, will ensure the compliance of the data processing in 
accordance with the provisions of Regulation (EU) 2016/679 (GDPR) and its transposition into French law 
(revision of files and civil liberties). 
10.2. Source data 
Any original document or object helping to prove the existence or accuracy of a piece of information or fact 
recorded during the study is defined as a source document. 
10.3. Confidentiality of data 
In accordance with the legislative provisions in force (articles L.1121-3 and R.5121-13 of the French Public 
Health Code), people with direct access to source data will take all necessary precautions to ensure the 
confidentiality of information related to the study and people taking part in them, particularly as regard 

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their identity and the results obtained. These people, like the investigators themselves, are subject to 
professional secrecy. 
During the study or when it is over, the information collected on the people taking part in it and forwarded 
to the sponsor by the investigators (or any other specialized staff member involved) will be coded in 
respect of confidentiality rules. Under no circumstances may the names or addresses of the people 
concerned appear in it. 
For coding subjects the first letter of the first name and first letter of the last name of the subject will be 
recorded, accompanied by a code showing the order of inclusion of the subject. 
The sponsor will ensure that each person taking part in the study has given his agreement in writing for 
access to only the individual data that are strictly necessary for quality control of the study. 
11. Quality Control and Insurance 
11.1. Instructions for collecting data 
All the information required by the protocol will be entered in an electronic case report forms and an 
explanation will be provided for each piece of information which is missing. 
The data must be collected as and when they are obtained, and transcribed into these forms in a clear and 
legible manner. Incorrect data must be clearly crossed out and the new data copied in beside the crossed-
out information, with the initials, date and possibly a reason, by the investigator or authorised person who 
has made the correction. 
11.2. Monitoring of the study 
The study will be monitored by a clinical research technician. He/she will be responsible for: 
 
The logistics of and monitoring the study, 
 
Producing reports concerning its state of progress, 
 
Verifying that the case report forms are updated (request for additional information, corrections, 
etc.), 
 
Sending samples, 
 
Transmitting SAEs to the sponsor. 
 
He/she will work in accordance with the standard operating procedures, in cooperation with the clinical 
research associates appointed by the sponsor. 
11.3. Quality control 
A clinical research associate appointed by the sponsor will regularly visit each study centre during the 
process of setting up the study, one or more times during the study depending on the frequency of 
inclusions, and at the end of the study. During these visits, the following aspects will be reviewed: 

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 
informed consent 
 
compliance with the study protocol and the procedures set out in it 
 
the quality of the data collected in the case report form: its accuracy, missing data, consistency of 
the data with the source documents (medical records, appointment diaries, the originals of 
laboratory results etc.) 
Quality control will be performed according to the monitoring plan defined for this study and then, a 
monitoring report will be written. 
11.4. Data management 
Data management will be performed by the INSERM CIC-P 1415. An electronic Case Report Form (eCRF) will 
be developed using the Clinsight software. eCRF management will be managed in agreement with the 
INSERM CIC-P 1415 Standardized Operating Procedures (SOP). CRA in charge of the study will be formed to 
the e-CRF and in charge of the physicians’ formation. Data will be entered in investigating centres through a 
secure web site, monitored by CRAs and queries will be edited by data-managers, in agreement with an a 
priori specified data-management plan.  
A blind review will be done prior locking the data-base. The data-base will be locked in agreement with the 
INSERM CIC-P 1415 SOPs and data will be extracted in a SAS format or other, according to statistical 
requirements. Raw data will be stored in a XML format. 
The query of the hospital databases (FNHDD) will take place at the end of the study. This step will include 
all patients stay data from randomization to day 28. The data will be requested by UEME and the main 
investigator from the medical information department of each centre.  
The link between the patient's identity and their study code will be made in each centre to preserve 
confidentiality. UEME will not have access to the patient's identity. 
11.5. Audit and inspection 
An audit may be performed at any time by people appointed by the sponsor who are independent of those 
responsible for the study. The aim of an audit is to ensure the good quality of the study, that its results are 
valid and that the law and regulations in force are being observed. 
The investigators agree to comply with the requirements of the sponsor and the relevant authority for an 
audit or an inspection of the study. 
The audit can apply to all stages of the study, from development of the protocol to publication of the 
results and filing the data used or produced in the study. 
12. Storage of documents and data concerning the study 
The following documents relating to this study are archived in accordance with Good Clinical Practice: 
 

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By the investigating doctors: 
- For a period of 15 years following the end of the study 
• The protocol and any amendments to the protocol 
• The case record forms  
• The source files of participants who signed a consent form 
• All other documents and letters relating to the study 
- For a period of 30 years following the end of the study 
• The original copies of informed consent forms signed by participants 
The investigator is responsible for all these documents for the regulation period of archiving.  
 
By the sponsor: 
- For a period of 15 years following the end of the study 
• The protocol and any amendments to the protocol 
• The originals of the case record files  
• All other documents and letters relating to the study 
- For a period of 30 years following the end of the study 
• A copy of the informed consent forms signed by the participants 
• Documents relating to serious adverse events 
The sponsor is responsible for all these documents for the regulation period of archiving. 
 
No removal or destruction may be carried out without the sponsor's agreement. At the end of the 
regulation archiving period, the sponsor will be consulted regarding destruction. All the data, all the 
documents and reports could be subject to audit or inspection. 
13. Rules relating to publication 
13.1. Scientific communication 
Analysis of the data provided by the study centres will be performed by INSERM CIC-P 1415 Tours and the 
UEME, Tours. This analysis will result in a written report that will be submitted to the sponsor, who, in turn, 
shall transmit it to the ethics committee and the relevant authority. 
Any written or oral communication of the results of the study must have been previously agreed by the 
coordinating investigator and, if necessary, by any committee constituted for the study. 
Publication of the main results will mention the name of the sponsor, all the investigators who recruited or 
monitored patients in the study, the methodologists, biostatisticians, economists and data managers who 
took part in the study, the members of the committee or committees set up for the study and the source of 

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finance. The international rules for writing and publication (Vancouver Agreement, February 2006) will be 
taken into account. 
 
Primary publication ranking rule will be the following:  
- 
First author: one investigator from the CHR of Orléans, the initiator of the project 
- 
Second author: Investigator from highest recruiter site 
- 
Third author: Investigator from second highest recruiter site 
- 
Other authors up to the number of authors authorized by the targeted journal: depending both on 
recruitment and scientific involvement in the project 
- 
Places of methodologist and economist: to be determined 
- 
Senior (last) author: one investigator from the CHR of Orléans 
13.2. Communication of the results to patients 
In accordance with the law n° 2002-303 of 4th March 2002, patients will be informed, at their request, of 
the overall results of the study. 
13.3. Ceding data 
The collection and management of data will be carried out by CHR of Orléans. The conditions for ceding all 
or part of the database of the study will be decided by the sponsor of the study and will be the subject of a 
written contract. 
14. Costs and payments 
14.1. Study costs 
There will be no additional costs to subjects as part of this study. The only additional study costs above 
what is considered to be standard hospital care. Subjects and their insurers or third party payers will not be 
billed for research related services. All research related services will be paid for by the sponsor. 
14.2. Study payments 
Research subjects will receive no payments or other remuneration for their participation in the study. 
15. Evaluation of security 
As this research is involving person with minimal risk (non-invasive blood pressure), all serious adverse 
event, in accordance with regulations in force, have to be reported by the investigator according with each 
procedure in place for reporting adverse event related to care in the institution. According to the article 
L1123-10 of the French Public Health Code, in this low risk study (as defined by the article L1121-1), SAEs 
are not to be declared within 24 hours but are to be collected and registered in the source documents and 

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study CRF. 
The following AEs will be considered SAEs of special interest and are to be recorded in source documents 
and study CRF, whatever their relation to the study procedures and whatever the study arm the patient is 
assigned to: 
- Ischemia and/or necrosis of finger(s) or toe(s) 
- Documented bowel ischemia 
- Occurrence or worsening of acute renal failure with need of renal replacement therapy (while there 
was no need of renal replacement therapy before this event) 
- Need of tracheal intubation in a patient previously not intubated 
- Cardiac arrest 
- Death of any cause 
Each adverse event, serious or not, related or not to the study procedure have to be recorded in source 
documents and study CRF.  
 
For safety purpose, the following AEs that could potentially be related to the BP measuring method used, 
will be systematically collected in source documents and study CRF (not to be declared in real time): 
- 
nerve injury of upper limb(s) 
- 
skin lesions at cuff location or at IAC insertion site 
- 
arterial thrombosis 
- 
hematoma 
- 
arterial pseudo aneurysm 
- 
haemorrhage at IAC insertion site either during IAC placement or later 
16. Committees 
16.1. Scientific committee 
It is composed of members of the scientific committee of the CRICS group and wrote the protocol. 
16.2. Data Safety Monitoring Board 
For this research that brings minimal risks (in the meaning of the French Law), we do not plan to set up an 
independent Data Safety and Monitoring Board. 
17. Budget Evaluation 
17.1. Budget of the study 
The study budget will be coordinated by the sponsor, the university hospital centre of Tours. A financial 
convention will be signed between each participating centre and the sponsor. 

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17.2. Compensation for participants 
No compensation for participants is planned. 

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18. Bibliography 
1. 
Gershengorn HB, Garland A, Kramer A, Scales DC, Rubenfeld G, Wunsch H. Variation of arterial and 
central venous catheter use in United States intensive care units. Anesthesiology. 2014 
Mar;120(3):650–64.  
2. 
Vincent J-L, Bihari DJ, Suter PM, Bruining HA, White J, Nicolas-Chanoin MH, et al. The prevalence of 
nosocomial infection in intensive care units in Europe. Results of the European Prevalence of 
Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA. 1995 
Aug;274(8):639–44.  
3. 
Boulain T, Boisrame-Helms J, Ehrmann S, Lascarrou J-B, Bouglé A, Chiche A, et al. Volume expansion 
in the first 4 days of shock: a prospective multicentre study in 19 French intensive care units. 
Intensive Care Med. 2015 Feb;41(2):248–56.  
4. 
Angus DC, Shorr AF, White A, Dremsizov TT, Schmitz RJ, Kelley MA. Critical care delivery in the 
United States: Distribution of services and compliance with Leapfrog recommendations*. Crit Care 
Med. 2006 Apr;34(4):1016–24.  
5. 
Traoré O, Liotier J, Souweine B. Prospective study of arterial and central venous catheter 
colonization and of arterial- and central venous catheter–related bacteremia in intensive care 
units*. Crit Care Med. 2005 Jun;33(6):1276–80.  
6. 
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: 
international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 
2013 Feb;41(2):580–637.  
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blood gas and lactate from central venous blood analysis in critically ill patients: a multicentre, 
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19. APPENDIX 1 
 
In both groups, once the patient alert and capable, we will assess his/her pain and discomfort 
related to the BP measuring device in place. 
 
Whatever the group the patient is assigned to, he/she will rate, once a day, his/her pain and 
discomfort using the following 11-point numerical scales. 
 
• 
Does the presence of the BP measuring device (catheter or cuff) cause you some discomfort?  
To be rated from 0 (no discomfort at all) to 10 (very important and permanent discomfort). 
 
• 
Does the presence of the BP measuring device (catheter or cuff) cause you some pain, either 
continuous of intermittent, at the site of measurement (location of catheter or of cuff)?  
To be rated from 0 (not painful at all) to 10 (highest pain ever experienced). 
 
• 
Does the presence of the BP measuring device (catheter or cuff) cause you some pain, either 
continuous of intermittent, that extends beyond the site of measurement and spreads over the 
entire limb? 
To be rated from 0 (not painful at all) to 10 (highest pain ever experienced). 
 
• 
Does the presence of the BP measuring device (catheter or cuff) cause you some numbness in the 
hand (or in the foot; depending upon location of the BP measuring device)?  
To be rated from 0 (no numbness at all) to 10 (highest numbness ever experienced). 
 
 
 
 

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Pre-test 
probability 
Post-test 
probability 
Likelihood 
ratio 
The following pages provide diagrams to help estimate true values of arterial 
blood gases (pH, PaCO2, SaO2) and lactate, using central venous blood analysis, 
SpO2, and, only for pH, clinical characteristics. 
Functions used to calculate these estimates were derived and validated in a large 
cohort of ICU patients (Boulain et al, Br J Anaesth 2016 117 :341–9). 
In each diagram, the user will find upper and lower red and blue lines that 
delineate, for each predicted value, thresholds above which (for upper lines) or 
below which (for lower lines) the true arterial value is very unlikely to be, i.e.,  
the threshold closest to the predicted value yielding a negative likelihood ratio 
with upper 95% confidence interval boundary below 0.1 (for redlines) or below 
0.05 (for blue lines). 
To help the user it is worth reminding how to interpret likelihood ratios, and 
particularly that their clinical value will depend upon the clinical context, i.e., 
whether and how much an arterial value is likely to be abnormal. For instance, a 
COPD patient with encephalopathy and flapping tremor is likely to have 
abnormally high PaCO2, whereas a patient without past medical history 
presenting open femoral fractures and haemorrhagic shock is likely to have 
normal or decreased PaCO2. 
For a pre-test probability of 50% (no idea what the true value could be), a 
negative likelihood ratio of 0.1 or below results in a post-test probability of 8% or 
less (thin orange line on Fagan’s diagram as shown on right side of this page). 
For a pre-test probability of 50%, a negative likelihood ratio of 0.05 or below 
results in a post-test probability of 5% or less (thick orange line). 
If the a priori probability of observing a normal true arterial value is deemed 
rather low (say pre-test probability of 10%), the post-test probability will be 
very low (1% or 0.5%) for a negative likelihood ratio of 0.1 or of 0.05 (thin and 
thick green lines, respectively) 
Remember, diagrams and likelihood ratios given in the following pages should 
always be interpreted according to the clinical context. 
20. APPENDIX 2 
 
 

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1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
LACTATE 
For each predicted lactate value: 
- true lactate value is not above the upper red line 
with high degree of certainty ( upper boundary of 
95% confidence interval ofthe negative likelihood ratio 
is below 0,1) 
-  true lactate value is not above the upper blue line 
with very high degree of certainty ( upper boundary 
of 95% confidence interval of the negative likelihood 
ratio is below 0,05) 
Predicted arterial lactate (mmol/L) 
True arterial lactate (mmol/L) 
Predicted arterial Lactate= 
13.8923−(1.8323×pHcv)
−(0.0139×PcvCO2)−(0.0023×ScvO2)+(0.9520
×Lactcv) 
For each predicted lactate value: 
- true lactate value is not below the lower red line with 
high degree of certainty (upper boundary of 95% 
confidence interval of the negative likelihood ratio is 
below 0,1) 
- true lactate value is not below the lower blue line 
with very high degree of certainty ( upper boundary of 
95% confidence interval ofthe negative likelihood ratio is 
below 0,05) 
 

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pH 
6,70 
6,80 
6,90 
7,00 
7,10 
7,20 
7,30 
7,40 
7,50 
7,60 
6,70 
6,80 
6,90 
7,00 
7,10 
7,20 
7,30 
7,40 
7,50 
7,60 
For each predicted pH value: 
- true arterial pH is not above the upper red line with high 
degree of certainty (upper boundary of 95% confidence 
interval ofthe negative likelihood ratio is below 0,1) 
-  true arterial pH is not above the upper blue line with very 
high degree of certainty (upper boundary of 95% confidence 
interval of the negative likelihood ratio is below 0,05) 
For each predicted pH value: 
- true arterial pH is not below the lower red line with high degree 
of certainty (upper boundary of 95% confidence interval of the 
negative likelihood ratio is below 0,1) 
- true arterial pH is not below the lower blue line with very high 
degree of certainty (upper boundary of 95% confidence interval 
ofthe negative likelihood ratio is below 0,05) 
Predicted arterial pH = 
1.0649+(‘Chronic heart failure’×0.0052) +(‘Liver 
cirrhosis’×−0.0089)+(‘vasopressor dosage’× −0.0061) 
+(pHcv×0.8693)+(Lactcv×−0.0019)+(PcvCO2×−0.0008) 
+(ScvO2×−0.0008)+(SpO2× 0:0003) 
True arterial pH  
Predicted arterial pH  

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20 
25 
30 
35 
40 
45 
50 
55 
60 
65 
70 
75 
80 
85 
90 
95 
20 
25 
30 
35 
40 
45 
50 
55 
60 
65 
70 
75 
80 
85 
90 
95 
PaCO2 
For each predicted PaCO2 value: 
- true PaCO2 is not above the upper red line with 
high degree of certainty (upper boundary of 95% 
confidence interval ofthe negative likelihood ratio is 
below 0,1) 
-  true PaCO2 is not above the upper blue line with 
very high degree of certainty (upper boundary of 
95% confidence interval of the negative likelihood 
ratio is below 0,05) 
For each predicted PaCO2 value: 
- true PaCO2 is not below the lower red line with high degree of certainty 
(upper boundary of 95% confidence interval of the negative likelihood ratio is 
below 0,1) 
- true PaCO2 is not below the lower blue line with very high degree of 
certainty (upper boundary of 95% confidence interval ofthe negative likelihood 
ratio is below 0,05) 
Predicted PaCO2= 
96.3474+(−12.3695×pHcv)+(0.6877×PcvCO2 ) 
−(0.0209×PcvO2)+(0.1987×ScvO2) −(0.4768×Lactcv) 
−(1060 × SpO2) 
True PaCO2 (mmHg) 
Predicted PaCO2 (mmHg) 
 

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87 
88 
89 
90 
91 
92 
93 
94 
95 
96 
97 
98 
99 
100 
87 
88 
89 
90 
91 
92 
93 
94 
95 
96 
97 
98 
99 
100 
SaO2 
For each predicted SaO2 value: 
- true SaO2 is not above the upper red 
line with high degree of certainty 
(upper boundary of 95% confidence 
interval ofthe negative likelihood ratio 
is below 0,1) 
-  true SaO2 is not above the upper 
green line with very high degree of 
certainty (upper boundary of 95% 
confidence interval of the negative 
likelihood ratio is below 0,0001) 
For each predicted PaCO2 value: 
- true PaCO2 is not below the 
lower red line with high degree 
of certainty (upper boundary of 
95% confidence interval of the 
negative likelihood ratio is below 
0,1) 
- true PaCO2 is not below the 
lower green line with very high 
degree of certainty (upper 
boundary of 95% confidence 
i nterva l of t he negative 
likelihood ratio is below 0,0001) 
Predicted SaO2= 
49.2238+(2.4000×pHcv)−(0.0276×PcvCO2) 
+(0.0883×ScvO2 )−(0.2479 × SpO2) 
True SaO2 (%) 
Predicted SaO2 (%) 
 

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