Clinical trial NCT02973048
Conditions: Pregnant Women Pain Hypotension
Keywords: Cesarean delivery Spinal anesthesia Local anesthetics
Sponsor: Centre Hospitalier Universitaire Saint Pierre
Start date: 2018-03-12; Completion date: 2018-11-08
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Over the past 15 years, cesarean delivery is most commonly performed under spinal anesthesia using hyperbaric bupivacaine which provides an adequate sensory and motor block. Despite effective surgical anesthesia, bupivacaine is associated with long duration motor block and dose-dependent maternal hypotension potentially harmful for the fetus. Prilocaine with its new 2% hyperbaric formulation (HP), developed recently, showed rapid onset of action and faster regression of motor block compared to other local anesthetics without noteworthy side-effects when used intrathecally. The aim of this randomized, multicenter, powered clinical trial is to investigate whether HP may be an efficient alternative to hyperbaric bupivacaine for scheduled caesarean delivery under spinal anesthesia, with more rapid rehabilitation and less adverse effects. Our hypothesis is that hyperbaric prilocaine offers shorter motor block and more rapid rehabilitation than bupivacaine.

Detailed description:

Arms: arm 1: Hyperbaric bupivacaine 0.5% will be administered at the dose of 10 mg intrathecally associated with 100 µg of morphine and 2.5 µg of sufentanyl. arm 2: Hyperbaric prilocaine 2% will be administered at the dose of 50 mg intrathecally associated with 100 µg of morphine and 2.5 µg of sufentanyl.
Interventions: intervention 1: Hyperbaric bupivacaine intervention 2: Hyperbaric prilocaine
Intervention descriptions: intervention 1: The dose of 10 mg of hyperbaric bupivacaine will be administered to one of two groups intrathecally and the quality of sensory and motor block as well as side-effects will be observed at precise time points. intervention 2: The dose of 50 mg of hyperbaric prilocaine will be administered to one of two groups intrathecally and the quality of sensory and motor block as well as side-effects will be observed at precise time points.

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL B076201627677 
 
 
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PROTOCOL B076201627677 (NTC02973048) 
 
Intrathecal hyperbaric bupivacaine 0,5% versus intrathecal 
hyperbaric prilocaine 2% for scheduled cesarean section 
 
 
 
 
 
 
 
 
 
Sponsor  
 
Centre Hospitalier Universitaire Saint-Pierre 
Rue Haute, 322 
1000 Bruxelles 
Belgium 
 
 
Principal 
Investigator  
 
Prof Panayota Kapessidou 
 
 
 
EudraCT 
number  
 
 
2016-003010-26  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PROTOCOL B076201627677 
 
 
Protocol Version 2.0-2017-11-02                                                                                                        2 
 
Sponsor signature page  
 
 
Study Title  
 
Intrathecal hyperbaric bupivacaine 0,5% versus intrathecal 
hyperbaric prilocaine 2% for scheduled cesarean section  
 
 
 
Protocol 
version   
 
 
Version 2.0 dated 2017-November-02                                                                
 
 
EudraCT 
number  
 
 
2016-003010-26 
 
Sponsor 
 
 
Prof Panayota Kapessidou 
 
 
Centre Hospitalier Universitaire Saint-Pierre 
Rue Haute, 322 
1000 Bruxelles 
Belguim 
 
 
 
 
 
                    
Signature, date 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
 
 
1. INTRODUCTION ..................................................................................................... 4 
2. MATERIAL AND METHOD  ...................................................................................... 5 
2.1 Population   ........................................................................................................... 5 
 
2.2 Anaesthesia plan  .................................................................................................. 6 
2.2.1 Preoperative ................................................................................................. 6 
2.2.2 Peroperative ................................................................................................. 6 
2.2.3 Postoperative  ............................................................................................... 7 
 
2.3 Satistical analysis method  ..................................................................................... 7 
 
2.4 Collect of the data  ................................................................................................ 7 
2.4.1 Patients ......................................................................................................... 7 
2.4.2 Central block (spinal injection) ....................................................................... 8 
2.4.3 Surgical variables ........................................................................................... 8 
2.4.4 Haemodynamic variables............................................................................... 8 
2.4.5 Ventilation, state of conciousness.................................................................. 8 
2.4.6 Secondary effects .......................................................................................... 9 
2.4.7 Post-operatory analgesia ............................................................................... 9 
2.4.8 New born ...................................................................................................... 9 
2.4.9 Quality of the technic .................................................................................... 9 
 
3. BIBLIOGRAPHY  ..................................................................................................... 10 
 
 
 
 


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1. INTRODUCTION 
 
 
In case of scheduled cesarean section, intrathecal anaesthesia, in the absence of 
contraindications, is the choice of anesthetic technique (1). This procedure is simple to 
perform and involves the administration of local anaesthetic with or without adjuvant, 
into the subarachnoidal space surrounding the spinal nerves and the spinal cord. It leads 
to a rapid onset of surgical anesthesia with a good quality motor and sensory nerve 
block to let the surgeons do their surgery in good conditions as well for the patient (2). 
So, it allows the parent, the mother in particular, to have a better experience of the 
delivery during the c-section. 
Nevertheless, there are secondary effects due to this procedure and the local 
anaesthetics. Principally, haemodynamics effects such as major low blood pressure can 
decrease the utero-placental perfusion and cause nausea and vomiting (3,4). The 
outcome of the newborn is essentially related to the duration of maternal hypotension 
(5,6). Some prophylactics measures or treatements are taken, such as preloading 
perfusions, mother’s position (left tilt) and the use of vasopressors drugs (ephedrine, 
phenylephrine) (3,4,7), but their efficacity remains questionable (8). Today, the studies’ 
authors agree on the fact that the haemodynamics effects of the intrathecal injection are 
directly linked to the dose of the local anaethetic (9). 
 
For over 30 years, hyperbaric bupivacaine 0,5%, an amide-type local anesthetic 
of long action time, is the most used drug for spinal injection in c-section, associated to 
opiods (sufentanyl or fentanyl and morphine) (10,11). However, its use is frequently 
followed by haemodynamical instability and by a motor nerve block of long duration, 
two factors that lead to an increased fœtal risk and maternal discomfort (12). 
 
The arrival on the market of newer short and intermediate duration time local 
anaesthetics such as chloroprocaine and prilocaine, seems to offer a good alternative for 
hyperbaric bupivacaine (13). This coincides with practice trends in anaesthesia for more 
ambulatory perioperative pathways and to a fast track rehabilitation in every speciality, 
obstetrics included. 
 
 
Prilocaine, in particular, since its recent marketing into its stable hyperbaric 
form, has already been used for spinal injection in many studies in orthopedic surgery, 
gynaecologic surgery, and urologic surgery where it permitted a good quality nerve 
blockade with less secondary effects (14, 15). Its use, indeed, has shown a rapid onset 
anaesthesia (from 8 to 18 minutes maximum), a shorter action during time compared to 
the bupivacaine and a faster motor block offset in postoperative time, determined at 118 
minutes (16). 
 
In obstetrics, the former prilocaine isobaric form has been used only for epidural 
analgesia for the labour and vaginal delivery. Nevertheless, newborn high 
methemoglobinemia has been observed, due to long time epidural perfusion, at elevated 
doses in a range of 5,4-6,7 mg/kg (higher doses than 600mg) (17). Recently, hyperbaric 
prilocaine, without opiods adjuvants, has been used for c-section surgery in intrathecal 
injection in a pilot study realised to determine the efficacity dose 95 (ED95) (18). The 
results seem to be promising. 


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Until now, no study has ever compared prilocaine versus bupivacaine in spinal 
injection for c-section. 
 
 
Our primary goal is to analyse the place of hyperbaric prilocaine 2% in a context 
of scheduled cesarean section by a power comparison study versus hyperbaric 
bupivacaine 0,5%, to find the most efficient one with a shorter action time and less 
secondary effects between this two local anaethetics. 
 
2. MATERIAL AND METHOD 
 
It is a prospective, randomised (double blinded), multicentric study, with 
parturients undergoing scheduled cesarean section performed with intrathecal 
anaesthesia. 
 
2.1. Population  
 
Patients will be included in the study, after reading, understanding and accepting 
the document explaining the goals and the procedure of the study protocol and signing 
their consent. The study will proceed in the department of Anesthesiology-Reanimation 
of the CHU Saint-Pierre and in the department of Anesthesiology of the Hospital Sainte-
Anne Saint-Rémi in collaboration with their respective department of obstertrics. The 
number of patients to be included in this study has been determined by a power study 
based on previous results. The trial will be end when a sample of 100 parturients will 
undergo a scheduled cesarean section performed with intrathécal anaesthesia. 
The primary goal is to compare prilocaine with bupivacaine usually used in spinal 
injection; parturients will be assigned after randomisation into 2 groups: 
 
G1 : Hyperbaric Bupivacaine 10 mg (Marcaine®) 
G2 : Hyperbaric Prilocaine 50 mg (Tachipri ®) 
 
To each dose will be added 2.5 µg of sufentanyl and 100 µg of morphine and the 
total injected volume will be identical for every group. 
 
 
Inclusion criteria 
- 
ASA < III 
- 
Age 18-40 year 
- 
Weight <110 kg 
- 
Height between 160 and 175 cm 
- 
Gestational age>37 SA 
- 
Scheduled cesarean section 
- 
Single fetus 
- 
Non complicated pregnancy 
 
Exclusion criteria 
- 
Twin pregnancy 
- 
History of 2 cesarean section or more 
- 
Diabetes and gestational diabetes 
- 
Placenta praevia 


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- 
Congenital foetale abnormality 
- 
Patient in labour 
- 
Membrane rupture 
- 
Allergy to local anaesthetics 
- 
Disagreement of the patient 
- 
Gestational low blood pressure 
- 
Pre eclampsia and eclampsia 
 
2.2. Anaesthesia plan  
 
Preoperative : 
Patients will undergo a combined spinal and epidural anaesthesia, to allow for 
supplementation of the anesthesia in case incomplete or insufficient blockade.  
 
2.2.1. Preoperative  
 
-  Premedication : PO ranitidine 300mg the day before, in the morning PO ranitidine 
150mg and PO metoclopramide 10mg 30 minutes before the combined anaesthesia, PO 
citrate of sodium 30ml before the operating room. 
-  Coagulation test, full blood count, blood group, cross match and irregular antibodies 
check, and renal tests  
-  Miction before the operating room, evaluation of the bladder volume (Bladderscan) 
before the intrathecal anaesthesia in the operating room. 
 
2.2.2. Peroperative  
 
- Monitoring :  
ECG, NIBP, pulse oximetry (SpO2), peripheral venous access 18G or 16G, urinary 
catheter, Bair hugger. 
 
- Realisation of the combined anaesthesia : 
Vascular co-loading with 1000ml of Hartmann solution. 
The patient is in a sitting position, L3-L4 level is localised. With a Vygon combined 
anesthesia set, the epidural space is reached with a Tuohy 8 cm needle, 17G with a low 
resistance syringe filled with saline. Then, a 29G needle is used through the Tuohy 
needle to access to the spinal space ; once the cephalo-spinal liquid reflux is positive, the 
test solution with 100 µg of morphine is injected into the spinal space in 
approximatively 20 seconds. Then an epidural multiperforated catheter is introduced 
until 3-4 cm in the epidural space, an aspiration test is done but no test dose is injected. 
The patient is placed, after 5 minutes minimum of the intrathecal injection, in supine 
position with a left tilt and 3l/min of nasal O2. 
Every patient receive, after randomisation, a predetermined local anaesthetic dose 
(bupivacaine or prilocaine). 
 
- Nerve blocade evaluation : 
The evaluation of the sensitive level will be realised by a pressure test, a cold test and a 
pin-prick test. 
 
 


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The block will be considered as a : 
- 
SUCCESS : bilateral T4 level reached in 15 minutes after intrathecal injection 
without additional epidural injection needed within 45 minutes peroperative ; no 
pain at the skin incision, no pain during 45 minutes after the skin incision. 
- 
FAILURE : level < T4 at 15 minutes after the intrathecal injection or the 
additional epidural injection needed during the cesarean section (lidocaine 2% 
with epinephrine) by 5ml/5minutes for a VAS< 3. 
 
- Low blood pressure evaluation : 
As low blood pressure, we define a blood pressure lower than 20% or more than the 
basal blood pressure (Systolic BP before spinal anesthesia). 
Treatment : Ephedrine 5mg/ml, phenylephrine 100 µg/ml by titration (ml by ml); blood 
pressure goal : Systolic BP before spinal injection -10%. 
 
2.2.3.  Postoperative  
 
-  Postoperative analgesia : Paracetamol + NSAID at the end of the surgery. 
- Removal of the urinary catheter : after complete offset of the motor block and a stand 
up trial (after a forced extention of the legs against resistance, about 3 hours after the 
intrathecal injection) ; and/or S2 level restored. 
- Monitoring of the bladder volume 1x/hour, by Bladderscan examination until first 
miction. 
In case of bladder retention, defined such as a bladder volume higher than 600ml, 
associated at a spontaneous miction, a bladder catherisation will be realised. 
- Walking : it will be asked to the patient to do a walking test (6 minutes walking test) 
with a minimum of 25 m to walk, 1h, 2h, 3h and 4h after a complete released of the 
motor block and a sensitive block lower than L5-S1. 
 
2.3. Statistical analysis method  
 
The primary outcome that will be analysed in this study is the time to motor 
block resolution after intrathecal injection of the two local anaesthetics. 
Every patient will receive, after randomisation, a dose of local anaesthetic (bupivacaine 
or prilocaine); the study will be powered to highlight a difference of 20% for the 
principal variable between the groups. 
 
2.4. Collect of the data  
 
2.4.1. Patients  
 
- 
Name, number of file, age, weight, height, BMI, parity/gestity, ethnicity, number 
of previous c-section, term. 
- 
Blood pressure, cardiac frequency, pre operatory SpO2 and before anesthesia. 
- 
Bladder volume before Spinal injection. 
 
 
 
 
 


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2.4.2. Central block (spinal injection)  
 
- 
Sensitive block : level (pressure test, cold and pin-prick) every 2 minutes after 
spinal injection for 15 minutes, then every 5 minutes until the end of the surgery, 
then every 30 minutes until the complete release of the sensitive block (T12-S1) ; 
- 
Time between spinal injection and reached of T4 level ; 
- 
Obtained level 5 minutes after spinal injection ; 
- 
Maximum sensitive level ; 
- 
Complete lifetime of the sensitive block ( as the period between maximun level 
and the regression to the level T12-S2) ; 
- 
Lifetime of an adequate anesthesia for surgery ( as the period between spinal 
injection and  a VAS≥3 or a sensitive level superior regressed below T4 ; 
- 
Lifetime of the complete anesthesia (as the period between spinal injection and a 
VAS≥0. 
- 
Motor block : Modified Bromage score ( from 1 to 6), before spinal injection, 10, 
15, 20 minutes after injection, then every 15 minutes until the end of the surgery, 
then every 30 minutes until the complete released of the motor block ( Bromage 
6) ; 
- 
Time of installation of the motor block ( time between spinal injection and 
maximum motor block or Modified Bromage score of 1) ; 
- 
Total lifetime of the motor block (time between maximal blockade/ Modified 
Bromage score 1 and a Modified Bromage score 6). 
 
2.4.3. Surgical variables 
 
- 
Time between spinal injection and skin incision ; 
- 
Time between spinal injection and placental delivery ; 
- 
Time between skin incision and placental delivery ; 
- 
Time between uterine incision and placental delivery ; 
- 
Lifetime of the surgery. 
 
2.4.4. Haemodynamic variables  
 
- 
BP ( BP/ 1’ for 15 minutes, then BP/2,5’ until the end of the surgery, BP/20’ in 
the awaking room), CF ; 
- 
Needs of vasopressors drugs, total dose of administrated vasopressor drugs 
(phenylephrine, ephedrine). 
 
2.4.5. Ventilation, state of conciousness  
 
- 
SpO2, respiratory frequency, situation of respiratory depression (RF< 
10c/minutes or SpO2< 95%) ; 
- 
State of conciousness every 10 minutes after the spinal injection for one hour. 
 
 
 
 
 
 


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2.4.6. Secondary effects  
 
- 
Pain :VAS at incision time, placental delivery time, peritoneal closing time, skin 
closing time and every 5’ during the c-section, then every 4 hours for 24h ; 
- 
Nausea/ Vomiting, Headache, Prurit from 15 minutes after spinal injection, then 
every 4 hours for 24h ; marked as : 0= no symptoms ; 1= symptoms with no 
treatment necessary ; 2= Symptoms present and treated ; 
- 
Total blood loss (ml) ; 
- 
Transcient neurologic symptoms at D0, D1, D3 and D15, Defined as pain or 
dysesthesia or both, showed after complete released of the block in the lower 
limbs (19). 
 
2.4.7. Post-operatory analgesia  
 
- 
Lifetime between the first administration of antalgic drugs after the spinal 
injection, doses of the administrated drugs by day et total of injections for 72h. 
 
2.4.8. New born  
 
- 
Fetal cardiac frequency at the admission, weight, Apgar score, pH of the ombilical 
cord, SpO2, methemoglobinemia ; 
- 
Time between skin incision and birth, time between birth and the end of the 
surgery. 
 
2.4.9. Quality of the technic  
 
- 
Time of the bladder catheterisation, time of the first miction, residual bladder 
volume between the end of the bladder catheterisation and the first miction, 
urinary retention ; 
- 
Walking time, possibility of doing the 6MWT and the number of meters achieved, 
1h, 2h, 3H and 4h after a complete recuperation of the motor block and a 
sensitive block below L5-S1 (after cold test and pin-prick test) ; 
- 
Maternal satisfaction about the anesthetic technic during the surgery. It will be 
evaluated at the arrival in the awaking room by two methods : a) with a visual 
analogic scale where 0 cm = very unsatisfied and 10 cm = very satisfied ; and b) 
patients who have beneficiated of a previous c-section, will be asked to answer 
the question if they prefere the actual technic, the previous technic or have no 
preference (20) ; 
- 
Maternal rehabilitation : it will be evaluated at D1, D2 and D3 in the 
hospitalization unit by two methods : a) with a visual analogic scale where 0 cm = 
very poor and 1à cm = excellent ; and b) with the QoR score (Quality of Recovery 
score) (20) ; 
- 
Obstetrician and midwife satisfaction with a four points scale (0= unsatisfied/ 
poor quality ; 1= low satisfaction ; 2= satisfied/ good quality ; 3= very satisfied/ 
very good quality ; 4= excellent). 
- 
Global cost of the technic 
 
 
 


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3. BIBLIOGRAPHY  
 
1- Jenkins JG, Khan MM. Anesthesia for caesarean section: a survey in a UK region 
from 1992 to 2002. Anesthesia 2003; 58:1114 – 1118 
2- Bernard Dalens: Traité d’anesthésie générale, A mise à jour périodiques. Arnette; 
2001 
3- Morgan P. Spinal anesthesia in obstetrics. Canadian Journal of Anesthesia 1995; 
42. 1145-63 
4- Ngan Kee WD, Khaw KS, Lee BB, et al. A dose-response study of prophylactic 
intravenous ephedrine for prevention hypotension during spinal anaesthesia for 
caesarean delivry. Anesth Analg 2000; 90:1390-1395 
5- Reynolds F, Seed PT. Anesthesia for Caesarean section and neonatal acid-base 
status: a mata-analysis. Anaesthesia 2005; 60:636-653 
6- Roberts SW, Leveno KJ, Sidawi JE, et al. Fetal academia associated with regional 
anesthesia for elective caesarean delivry. Obstet Gynecol 1995; 85:79-83 
7- Tercanli S, Schneider M, Visca E, et al. Influence of volume preloading on 
uteroplacental and fetal circulation during spinal anaesthesia for cesarean 
section in uncomplicated singleton pregnancies. Fetal Diagn Ther 2002; 17:142-
146 
8- Cyna AM, Andrew M, Emmett RS et al. Technques for preventing hypotension 
during spinal anaesthesia for caesarean section {review}. The Cochrane Library 
2007. 
9- Rout CC, Roke DA, LevinJ, Gouws E,  Reddy D. A reevaluation of crystalloid 
preload in the prevention of hypotension associated with spinal anesthesia for 
elective cesarean section. Anesthesiology 1993; 79: 262-9. 
10- Liu SS. Optimizing spinal anesthesia for ambulatory surgery. Reg Anesth 
1997;22:500-10 
11- Gautier P. et al, Comparison of the effects of intrathecal ropivacaine, 
levobupivacaine, and bupivacaine for caesarean section. BJA 2003; 91(5); 684-9. 
12- Van de Velde M, Van Schoubroeck D, Jani J, Teukens A, Missant C, Deprest J. 
Combined spinal-epidural anesthesia for cesarean delivry: dose dependent 
effects of hyperbaric bupivacaine on maternal hemodynamics. Anesthesia and 
Analgesia 2006; 103. 187-90. 
13- Förster JG, Rosenberg PH. Revival of old local anesthetics for spinal anesthesia in 
ambulatory surgery: Current Opinion in Anaesthesiology 2011; 24(6):633–7. 
14- Martinez-Bourio M, Arzuaga M, Quintana JM, et al. Incidence of transient 
neurologic symptoms after hyperbaric subarachnoid anesthesia with 5% 
lidocaine and 5% prilocaine. Anesthesiology 1998;88:624–8. 
15- Guntz E, Latrech B, Tsiberidis C, Gouwy J, Kapessidou Y. ED50 and ED90 of 
intrathecal hyperbaric 2% prilocaine in ambulatory knee arthroscopy.Can J 
Anaesth. 2014 Sep;61(9):801-7. 
16- Camponovo C, Fanelli A, Ghisi D, Cristina D, Fanelli G. A Prospective, Double-
Blinded, Randomized, Clinical Trial Comparing the Efficacy of 40 Mg and 60 Mg 
Hyperbaric 2% Prilocaine Versus 60 Mg Plain 2% Prilocaine for Intrathecal 
Anesthesia in Ambulatory Surgery: Anesthesia & Analgesia 2010;111(2):568–72. 
17- Frey B, Kehrer B. Toxic methaemoglobin concentrations in premature infants 
after application of a prilocainecontaining cream and peridural prilocaine. Eur J 
Pediatr 1999; 158(10):785–8. 


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18- Leloup R, Goffard Ph, Kapessidou Y. Estimation of the ED95 of Intrathecal 
Hyperbaric Prilocaine for Scheduled Cesarean Delivery: A Dose-finding study 
based on the Continual Reassessment Method, ESA (European Congress of 
Anesthesiology) 2015. 
19- Hampl KL, Schneider MC, Ummenhoffer W, Drewe J: Transient neurologic 
symptoms after spinal anesthesia. Anesth Analg 1995; 81:1148-53. 
20- Gregory L. Bryson et al., CAN J ANESTH 2007 / 54: 7 / pp 531–537.