Can Non Invasive Methods for Fluid Responsive Assessment Optimize Preventive Volemic Repletion in Order to Prevent Significant Hypotension After Spinal Anesthesia? A Randomized Trial
Phase: NA
Conditions: Hypotension and Shock, Excessive Amount of Blood / Fluid Infusion
Sponsor: Ente Ospedaliero Cantonale, Bellinzona

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Sponsor/Sponsor-
Investigator 
Ente Ospedaliero Cantonale 
Study Title: 
Can Non Invasive Methods for Fluid Responsive Assessment Optimize 
Preventive Volemic Repletion in Order to Prevent Significant Hypotension 
After Spinal Anesthesia? A Randomized Trial.   
Short Title/Study ID: 
Predict Fluid Responsiveness in Spinal Anesthesia. (CERU-1401) 
Protocol Version and 
Date: 
Version 1.8 (24 February 2014) 
Trial Registration: 
The study is currently registered in the official register of the National 
Institute of Health (NIH) on the site www.clinicaltrial.gov, where it is 
possible 
consult in detail the design of the clinical trial, the objectives, the criteria of 
enrollment and statistical study data. The official registration number is 
NCT02070276 and can be freely consulted starting from the homepage 
by entering the official register number in the "search" field. 
The study was further recorded c / o Kofam (Koordinationsstelle 
Forschung am Mensche) with the protocol number SNCTP000000500. 
Study Category with 
Rationale 
Study category: Procedural / Intervention. 
Background 
and 
Rationale: 
Spinal anesthesia is a widely used regional anesthesia techniqueused in 
everyday clinical practice. It consists of the injection of a local anesthetic 
in the dural sac to obtain an anesthetic block 
in the roots of the local spinal nerves. 
After spinal anesthesia there is a reduction in vascular resistance 
systemic, with risk of arterial hypotension; for this later 
spinal anesthesia appears to be essential to correct the volume status of 
patient through the administration of fluids - normally infused in 
empirical manner - possibly associated with the administration of 
amine, with the aim of increasing peripheral resistance. 
The purpose of the study is to test the hypothesis that the use of two 
non-invasive methods before performing a spinal anesthesia, 
compared with the standard method (empirical volume filling) may 
reduce the impact of arterial hypotension through adequate filling 
pre-procedural, avoiding at the same time a water overload. All 
this with the aim of ensuring the execution of spinal anesthesia 
in the safest possible way for the patient in clinical practice 
current. 

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Objective(s): 
In clinical practice today the execution of spinal anesthesia is performed 
without a preliminary study of the volemic status of the patient. The doctor 
monitors the vital signs stabilizing blood pressure only when the patient 
manifested signs or symptoms of hemodynamic instability. It is sometimes 
given empirically a bolus of fluids before and during the procedure, but 
without knowing the actual volume status of the patient, with potential 
risks related to fluid overload. 
For about ten years, the literature has shown the presence of invasive and 
non-invasive methods to predict fluid responsiveness based on the 
assumption of the Frank-Starling curve. Until now, however, have never 
been applied to such predictive parameters in the setting anesthesia in 
patients undergoing spinal anesthesia, and then to a procedure 
predictably at risk of hypotension can potentially be prevented/reduced in 
frequency and severity with a suitable filling Fluid challenge. Still, in such 
clinical settings has not been studied the usefulness of non-invasive 
methods which, although less accurate compared to the analysis of 
invasive parameters, appear to be useful in the reduction of hypotensive 
episodes potentially dangerous for the patient. 
The aim of this study is to determine whether two non-invasive methods, 
free from risk, readily reproducible and feasible at the bedside such as 
ultrasound study of the inferior vena cava and the PLRT may, if 
implemented systematically before the procedure, drive towards 
individualized optimization volume status of the patient , which can 
significantly reduce the incidence of hypotension after spinal anesthesia in 
adult patients is not critical. 
Outcome 
(if 
applicable, 
see 
Basisformular): 
Primary Outcome 
 
Secondary Outcome 
 
The primary objective is to quantify cases of arterial hypotension 
that come to occur following spinal anesthesia, comparing i 
patients brought to euvolemia according to the TTE and PLRT 
parameters compared 
to patients treated according to the current standard. For arterial 
hypotension, 
in accordance with the international standard definitions, a drop is 
defined 
of systolic blood pressure over 50 mmHg compared to conditions 
basal, an absolute systolic pressure value of less than 80 mmHg, 
an average arterial pressure below 60 mmHg or one 
clinically symptomatic hypotension (dizziness, pallor, sweating, 
nausea). 
The first secondary objective is to stratify the rate of hypotension 
in the three groups based on further variables (age over 60 years, 
recruitment) 
of antihypertensive therapy, ASA classification, patient position 
post-operative) to see if the effects are more visible in 
a specific population. 
A further secondary objective is to quantify the 
water supply between the three comparison groups, using the patients 
of the control group as a reference, to be able to assess whether 
filling techniques, titrates on echocardiographic and / or evaluation 
response to internal mobilization of liquids is associated with a 
less unnecessary administration of liquids. 
Study 
Design, 
see 
Basisformular: 
 
Primary purpose: Prevention 
Study phase: N / A 
Intervention model: Parallel Arms 
Number of arms: 3 
Masking: Single Blind 
Allocation: Randomized 
Endpoint Classification: N / A 
Enrollment: 380 [Anticipated] 

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Inclusion/Exclusion 
Criteria, 
see 
Basisformular: 
 
3.1 Inclusion criteria 
Non-critical adult patients, 
Patients with loco-regional anesthesia with spinal technique 
Patients in the election regime 
Patients classified as ASA I, ASA II and ASA III 
3.2 Exclusion criteria 
Patients already equipped or requesting blood pressure monitoring 
invasive (arterial catheter, Swann-Ganz catheter, catheter of 
Peak) 
Patients with pre-procedural hypotension, defined as finding in 
two consecutive measurements of PAs less than 80 mmHg or PAm 
60 mmHg 
Patients unable to give their informed consent for 
communication difficulties due to language barriers or processes 
congenital / acquired determining mental retardation or one 
any reduction in one's ability to understand or 
want to be able to give your informed consent to the study 
Patients in whom anesthesia is not possible 
spinal due to patient's refusal, due to technical difficulties in 
collecting, 
for pathological clinical conditions determining a high risk of 
peri-procedural complications. 
Patients with INR> 1.5 and / or aPTT in therapeutic range 
(understood as 
value over 1.5-2 times the patient's normal values), anti-activity 
Xa in therapeutic range. 
Patients with severe thrombocytopenia (<50 G / l) 
Measurements 
and 
Procedures: 
 
Randomized three-arm interventional study involving the enrollment of 
all non-critical patients who undergo spinal anesthesia for any clinical 
indication in our Service. The anesthetic choice of loco-regional 
anesthesia is decided by the anesthesiologists in the pre-assessment of 
the patient according to the current clinical practice, according to the 
type of operation and the patient's current clinical conditions. 
Study 
Product/Intervention 
according to KlinV, if 
applicable: 
 
Arm B 
Before performing spinal anesthesia as in arm A (considered the control 
arm) a trans-thoracic echocardiography is performed in order to assess 
the patient's volume status. If it is responsive to liquids, a standard 500 
ml infusion is given. The procedure is repeated until the patient is no 
longer responsive to liquids; at this point we proceed with spinal 
anesthesia. 
 
Arm C 
Before performing spinal anesthesia as in arm A (considered the control 
arm) what is called Passive Leg Raising Test (PLRT) is performed: in a 
passive manner the position of the bed is changed so as to bring the 
trunk from 45 ° at 0 ° and the legs consequently rising from 0 ° to 45 °. 
Some hemodynamic parameters are measured (arterial pressure, heart 
rate, etCO2): if the values increase by 5% the patient is considered 
responsive to liquids and a standard infusion of 500 ml of crystalloids is 
administered. The procedure is repeated until the patient is no longer 
responsive to liquids: at this point we proceed with spinal anesthesia. 

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Comparator(s) 
(if 
applicable): 
Arm A 
The current clinical standard for spinal anesthesia is considered; it is 
used as a control and statistical reference sample. Before anesthesia 
the patient is equipped to measure arterial pressure, the ECG, a 
peripheral venous route and a peripheral saturimetry are positioned. The 
blood pressure control is set as standard every 5 minutes until the spinal 
anesthesia procedure; the pressure sleeve is placed on the upper arm 
during spinal anesthesia. The patient's data and vital signs are recorded 
and an infusion of crystalloids (NaCl 0.9% or Ringer-acetate) is given 
with the administration of 500 ml during the whole procedure from arrival 
to "induction place" until the start of the surgical operation . 
 
Number 
of 
Participants 
with 
Rationale 
(if 
no 
Power 
Analysis 
conducted): 
A sample of 288 patients appears adequate to obtain a confidence 
interval of 0.95. Assuming an exclusion and loss rate at the follow-up of 
30% total, it is estimated necessary to include 370 patients (maximum 
error = 0.05, value of z = 1.96). 
Study Duration: 
One year from enrollment of the first patient until the expected number of 
participants is reached. Maximum duration 12 months. 
Study Schedule: 
Start of study: 1 June 2014 
Study deadline: 31 May 2015 
Investigator(s): 
Dr. med. Samuele Ceruti (Principal Investigator) 
Capoclinica Medicina Intensiva EOC 
 
 
Dr. med. Luciano Anselmi (Study Coordinator) 
Primario Anestesia EOC 
 
 
Ospedale Regionale di Bellinzona e Valli 
Servizio di Anestesia 
Via Ospedale 12 
6500 – Bellinzona 
091/811.91.11 
Study Centre(s): 
Single-center study 

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Statistical 
Analysis 
incl. Power Analysis 
 
Power analysis: 
The study power calculation was performed, considering a 25% 
reduction in the incidence of arterial hypotension after spinal anesthesia 
with each of the methods compared to the control group, consisting of 
patients subjected to unguided filling. 
 
Statistic analysis 
A randomization program will assign patients to one of the 3 arms of the 
study, assigning a code to the patient. The data will be initially collected 
on paper forms by researchers not involved in the randomization 
process. The data will then be transferred to an IT database and 
anonymized, so that the researcher performing the statistical analysis is 
blinded to the assignment arm. 
 
The results will be subjected to statistical analysis using the Student test 
for continuous variables with normal distribution, the Mann-Whitney test 
for non-normal distribution variables and the Chi-square test for 
dichotomous variables. A value of p <0.05 will be assumed to be 
significant. 
GCP Statement: 
The study is conducted in accordance with the written protocol, the 
Helsinki declaration, international GCPs and national and local legal 
regulations. 
 
Study Procedure/Flowchart with Timelines: Study specific Examinations have to be clearly 
identified 
June 1, 2014: enrollment begins 
March 31, 2015: enrollment deadline (estimated) 
May 31, 2015: protocol closure (estimated) 
 

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Risks/ Inconveniences, which are Study specific:  
To reduce the risk of exposing the patient to hypotensive episodes or excessive water overload, 
patients who were truly or potentially unstable were excluded, patients with cardiovascular diseases 
considered to be severe according to the classification of the American Society of Anestesiology (from 
ASA IV level included in then) and patients with mechanical ventilation. 
 
The methods used (TTE and PLRT) appear completely non-invasive and free of side effects12. 
 
The study therefore does not use drugs or experimental procedures and does not investigate a 
population at risk. On the contrary, it simply aims to compare the current clinical practice with two 
different protocols that use safe methods and without side effects, to minimize the risks of the same 
for patients: replace an empirical volume filling with a targeted and personalized based on the state 
patient volume. 
 
Coverage of Damages: Insurance (yes/no)? Sum? 
No 
 
Storage of Data-and Samples for Future Research Aims: yes/no?,  
No 
 
Ethical Considerations: 
 
If the study proves to be able to show statistical significance, it will be possible to perform the spinal 
anesthesia procedure more safely for the patient in terms of: a) lower rate of arterial hypotension, b) 
adequate fluid loading. 
 
It will also be possible to extend a future study (designed in a similar way) to more complex groups of 
patients, where the avoidance of arterial hypotension and excessive water overload can have a 
decidedly greater and more significant prognostic impact. 
 
It will also be possible to lay the foundations for evaluating new mini / non-invasive methods for 
assessing the patient's water status before the spinal anesthesia procedure (or even other similar 
procedures) in the future, always with the aim of reducing peri-procedural risks . 
 
 
The study is risk free as explained in the previous section on "study risks". 
 
 
The strengths of the methodology are: 
a) stratified randomization: the three study groups are randomized and adequately balanced for 
parameters such as age, ASA risk class, taking anti-hypertensive therapy. 
b) Early publication of the protocol: for the FDA (on the website www.clinicaltrial.gov) and for the 
Swiss Federation (on the website www.kofam.ch) the protocol is published before the start of 
enrollment. The study design is established first and not adapted to the results found, in order to be 
able to demonstrate the results with absolute significance, regardless of their value. 
c) Patients' progressiveness: patients will not be pre-selected for the purpose of adapting the protocol 
to the "best" patients for the study. All patients with all the features present in the inclusion criteria will 
be enrolled, without a rationalized choice a priori or a posteriori (subject to the exclusion criteria). 

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d) Safety for participants: it was decided to restrict the study as much as possible by focusing on a 
population of patients at low risk of complications in the event of arterial hypotension and / or water 
overload, in order to evaluate the usefulness of the procedures totally canceling the risks for patients. 
e) Single-Blinding: after the randomization phase, the patient's documents are totally anonymised and 
blinded to the type of study arm. It will therefore be possible to perform an analysis of the data in a 
completely separate and independent manner from the knowledge of the branch of belonging during 
the protocol. 
f) Per-protocol analysis / intention to treat: the data will be analyzed both globally and further by 
focusing on the patients actually studied as per protocol, without any element of lack of adherence. It 
will therefore be feasible to evaluate the rate of adherence to the protocol (with the possibility of 
determining the feasibility on the part of third parties) and the double analysis of patients actually 
studied as per protocol. 
The most relevant References:  
Kim HJ, Kim JS. A cardiovascular collapse following vigorous cough during spinal anesthesia. Korean 
J 
Anesthesiol. 
2013 
Dec;65(6 
Suppl):S49-50. 
doi: 
10.4097/kjae.2013.65.6S.S49. 
PubMed   PMID: 24478870 
 
Nogueira CS, Lima LC, Paris VC, Neiva PM, Otani ET, Couceiro Rde O, Burim F, Ferreira JA Jr, 
Cadecaro P. A comparative study between bupivacaine (S75-R25) and ropivacaine in spinal 
anesthesia for labor analgesia. Rev Bras Anestesiol. 2010 Sep-Oct;60(5):484-94. doi: 10.1016/S0034-
7094(10)70060-X. English, Portuguese. PubMed   PMID: 20863929 
 
Xu S, Wu H, Zhao Q, Shen X, Guo X, Wang F. The median effective volume of crystalloid in 
preventing hypotension in patients undergoing cesarean delivery with spinal anesthesia. Rev Bras 
Anestesiol. 
2012 
May-Jun;62(3):312-24. 
doi: 
10.1016/S0034-7094(12)70132-0. 
PubMed   PMID: 22656677 
 
Kaimar P, Sanji N, Upadya M, Mohammed KR. A comparison of hypotension and bradycardia 
following spinal anesthesia in patients on calcium channel blockers and β-blockers. Indian J 
Pharmacol. 2012 Mar;44(2):193-6. doi: 10.4103/0253-7613.93847. PubMed   PMID: 22529474 
 
Zöllei E, Bertalan V, Németh A, Csábi P, László I, Kaszaki J, Rudas L. Non-invasive detection of 
hypovolemia or fluid responsiveness in spontaneously breathing subjects. BMC Anesthesiol. 2013 
Nov 5;13(1):40. doi: 10.1186/1471-2253-13-40. PubMed   PMID: 24188480 
 
Tulli G. Pulse pressure variation and stroke volume variation for prediction of fluid responsiveness in 
critically ill patients. Crit Care Med. 2013 Jan;41(1):e11. doi: 10.1097/CCM.0b013e318270e5a1. 
PubMed   PMID: 23269163 
 
Monge García MI, Gil Cano A, Gracia Romero M, Monterroso Pintado R, Pérez Madueño V, Díaz 
Monrové JC. Non-invasive assessment of fluid responsiveness by changes in partial end-tidal CO2 
pressure during a passive leg-raising maneuver. Ann Intensive Care. 2012 Mar 26;2:9. doi: 
10.1186/2110-5820-2-9. PubMed   PMID: 22449292 
 
Cherpanath TG, Geerts BF, Lagrand WK, Schultz MJ, Groeneveld AB. Basic concepts of fluid 
responsiveness. 
Neth 
Heart 
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doi: 
10.1007/s12471-013-0487-7. 
PubMed   PMID: 24170232 
 
Vieillard-Baron A, Chergui K, Rabiller A, Peyrouset O, Page B, Beauchet A, Jardin F. Superior vena 
caval collapsibility as a gauge of volume status in ventilated septic patients. Intensive Care Med. 2004 
Sep;30(9):1734-9. Epub 2004 Jun 26. PubMed   PMID: 15375649 
 
Pinsky MR, Payen D. Functional hemodynamic monitoring. Crit Care. 2005;9(6):566-72. Epub 2005 
Nov 22. Review. PubMed   PMID: 16356240 
 
Lamia B, Ochagavia A, Monnet X, Chemla D, Richard C, Teboul JL. Echocardiographic prediction of 
volume responsiveness in critically ill patients with spontaneously breathing activity. Intensive Care 
Med. 2007 Jul;33(7):1125-32. Epub 2007 May 17. PubMed   PMID: 17508199 
 

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Muller L, Bobbia X, Toumi M, Louart G, Molinari N, Ragonnet B, Quintard H, Leone M, Zoric L, Lefrant 
JY; the AzuRea group. Respiratory variations of inferior vena cava diameter to predict fluid 
responsiveness in spontaneously breathing patients with acute circulatory failure: need for a cautious 
use. Crit Care. 2012 Oct 8;16(5):R188. [Epub ahead of print] PubMed   PMID: 23043910