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Intrathecal Paracetamol Before Spinal Anaesthesia With Chloroprocaine HCl 1% for Short Knee Procedures

Primary Purpose

Pain, Postoperative

Status
Completed
Phase
Phase 2
Locations
Switzerland
Study Type
Interventional
Intervention
30 mg Paracetamol 3% (1 mL)
60 mg Paracetamol 3% (2 mL)
90 mg Paracetamol 3% (3 mL)
Placebo, 0.9% saline solution
NIMP: Chloroprocaine HCl 1% (10 mg/mL), solution for injection
Sponsored by
Sintetica SA
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Pain, Postoperative

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Informed consent: signed written informed consent before inclusion in the study
  2. Sex, age and surgery: male/female patients, 18-80 years old (inclusive), scheduled for short duration (up to 40 min) knee procedures
  3. Body Mass Index (BMI): 18 - 32 kg/m2 inclusive
  4. ASA physical status: I-III
  5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study.

Exclusion Criteria:

  1. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study. Contraindications to spinal anaesthesia. History of neuromuscular diseases to the lower extremities
  2. ASA physical status: IV-V
  3. Further anaesthesia: patients expected to require further anaesthesia
  4. Allergy: ascertained or presumptive hypersensitivity to the active principles (paracetamol and/or ester type anaesthetics) and/or formulations' ingredients or related drugs, non-steroidal anti-inflammatory drugs and/or opioid derivatives; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers could affect the outcome of the study
  5. Chronic pain syndromes: patients with chronic pain syndromes taking opioids, anticonvulsant agents or chronic analgesic therapy
  6. Pain assessment: patients anticipated to be unable to make a reliable self-report of pain intensity
  7. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that may interfere with the aim of the study; ascertained psychiatric and neurological diseases, sepsis, blood coagulation disorders, severe cardiopulmonary disease, thyroid disease, diabetes, other neuropathies, history or evidence of heart failure. History of severe head trauma that required hospitalisation, intracranial surgery or stroke within the previous 30 days, or any history of intracerebral arteriovenous malformation, cerebral aneurism or CNS mass lesion
  8. Medications: medication known to interfere with the extent of spinal blocks for 2 weeks before the start of the study. Paracetamol formulations, other than the investigational product, for 2 weeks before the start of the study and during the study. Hormonal contraceptives for females are allowed. Anti-hypotensive, anti-bradycardia (e.g. ephedrine, atropine, Ringer's solution), anti-haemetic and anti-nausea medications will be allowed
  9. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval is calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study
  10. Drug, alcohol: history of drug or alcohol abuse according to the Investigator's opinion
  11. Pregnancy and lactation: positive pregnancy test at screening (if applicable), pregnant or lactating women [The pregnancy test will be performed to all fertile women and to all women up to 55 years old, if not in proven menopause (available laboratory test confirming menopause or surgically sterilised)]

Sites / Locations

  • Department of Anaesthesiology, Clinica Ars Medica

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

30 mg Paracetamol 3% (1 mL)

60 mg Paracetamol 3% (2 mL)

90 mg Paracetamol 3% (3 mL)

Placebo, 0.9% saline solution

Arm Description

30 mg Paracetamol 3% (1 mL), solution for injection, single dose by intrathecal injection (IT)

60 mg Paracetamol 3% (2 mL), solution for injection, single dose by intrathecal injection (IT)

90 mg Paracetamol 3% (3 mL), solution for injection, single dose by intrathecal injection (IT)

Placebo, 0.9% saline solution (1 mL, 2 mL or 3 mL), solution for injection, single dose by intrathecal injection (IT)

Outcomes

Primary Outcome Measures

Pain Intensity at Rest Evaluated Using a 0-100 mm VAS
The study primary efficacy measures will be the VAS scores at each predefined time-point after the anaesthetic intrathecal injection until eligibility for home discharge ( VAS scale is 0-100 mm, where 0 is no pain and 100 is maximum pain)

Secondary Outcome Measures

Pain at Rest AUCt1-t2
AUC t1-t2 is defined as the area under the pain intensity curve at the specified time-intervals
Pain at Rest AUClast
AUClast is defined as the area under the pain intensity curve from 0 h up to the last assessment time
Time to First Postoperative Analgesia (Level 1 or 2)
Postoperatively, patients will be administered an analgesic as needed. Post-operative analgesia could include Ketorolac i.v. [Toradol] 30 mg (level 1 analgesia) and/or Tramadol i.v. 1 mg/kg (level 2 analgesia). The administered analgesic (level 1 or 2), analgesic dose and intake frequency will be decided according to the reported surgery-related pain intensity. Post-operatively, patients were administered an analgesic, as needed. Post-operative analgesia could include Ketorolac i.v. [Toradol] 30 mg (level 1 analgesia) and/or Tramadol i.v. 1 mg/kg (level 2 analgesia).
Partecipants to Received Level 1 Analgesia
Partecipants to received Ketorolac i.v. [Toradol] 30 mg administration (level 1 analgesia)
Partecipants Received Level 2 Analgesia
Partecipants received Tramadol i.v. 1 mg/kg administration (level 2 analgesia)
Total Number of Partecipants Receiving Analgesic 1
Total number of partecipants receiving Ketorolac i.v. [Toradol] 30 mg
Total Number of Partecipants Receiving Analgesic 2
Total Number of Partecipants Receiving Tramadol i.v. 1 mg/kg
Percentage of Patients Requiring Analgesia in the First 2 h After Surgery End
Percentage of patients requiring analgesia (level 1 or level 2) in the first 2 h after surgery end
Percentage of Patients Requiring Analgesia in the First 4 h After Surgery End
Percentage of patients requiring analgesia (level 1 or level 2) in the first 4 h after surgery end
Percentage of Patients Requiring Analgesia From Surgery End Until Eligibility for Discharge
Percentage of patients requiring analgesia (level 1 or level 2) from surgery end until eligibility for home discharge
Percentage of Patients Requiring Level 1 Analgesia From Surgery End Until Eligibility for Discharge
Percentage of patients requiring level 1 analgesia from surgery end until eligibility for home discharge
Percentage of Patients Requiring Level 2 Analgesia From Surgery End Until Eligibility for Discharge
Percentage of Patients Requiring Level 2 Analgesia From Surgery End Until Eligibility for Home Discharge
Percentage of Patients Requiring Supplementary Analgesia, Other Than the Planned Level 1 or 2 Analgesia
Percentage of patients requiring supplementary analgesia, other than the planned level 1 or 2 analgesia
Percentage of Patients Requiring Rescue Anaesthesia
Percentage of patients requiring rescue anaesthesia
Time to Onset of Spinal Block (i.e. Time to Readiness for Surgery)
Spinal block/Readiness for surgery is defined as the presence of an adequate motor block (Bromage's score ≥ 2) and loss of Pinprick sensation, according to the Investigator's opinion. Time to readiness for surgery is defined as the time from the spinal injection (time 0 h) to achievement of readiness for surgery.
Maximum Sensory Block
Maximum level of sensory block
Time to Sensory Block
Time to maximum level of sensory block (bilateral Pinprick test using a 20-G hypodermic needle)
Time to Regression of Spinal Block
Time period from spinal injection to the complete regression of sensory block to S1.
Time to Ambulation
Time to unassisted ambulation
Time to First Urine
Time to first spontaneous urine voiding
Time to Eligibility for Discharge
Time to eligibility for home discharge

Full Information

First Posted
January 23, 2018
Last Updated
June 1, 2021
Sponsor
Sintetica SA
Collaborators
Cross Research S.A.
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1. Study Identification

Unique Protocol Identification Number
NCT03428230
Brief Title
Intrathecal Paracetamol Before Spinal Anaesthesia With Chloroprocaine HCl 1% for Short Knee Procedures
Official Title
Dose-finding Study of Intrathecal Paracetamol Administered Immediately Before Spinal Anaesthesia With Chloroprocaine HCl 1% for Elective Knee Procedures of Short Duration
Study Type
Interventional

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
August 6, 2018 (Actual)
Primary Completion Date
October 22, 2019 (Actual)
Study Completion Date
October 22, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sintetica SA
Collaborators
Cross Research S.A.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a phase II, single centre, randomised, parallel-group, double-blind, three doses, placebo-controlled, exploratory efficacy and safety study. The objective of this study is to investigate the efficacy and safety of a single intrathecal injection of Paracetamol 3% (30 mg/mL) administered at 3 doses to 3 active treatment groups, as compared to placebo, for post-operative analgesia in knee procedures up to 40 min duration performed under spinal anaesthesia with Chloroprocaine HCl 1%.
Detailed Description
Eligible patients undergoing elective short-duration knee procedures up to 40 min duration will be randomised into 4 treatment groups (15 patients per group) to receive either one of the 3 single doses of Paracetamol 3% (D1: 30 mg, D2: 60 mg, D3: 90 mg) or the placebo solution (P: 0.9% saline solution) by intrathecal injection (IT), according to the randomised, parallel-group design. Immediately after IT paracetamol or placebo administration, all patients will receive a single IT dose of Chloroprocaine HCl 1% (Non-investigational medicinal product, NIMP) according to the Summary of Product Characteristics indications. The time interval between paracetamol IT and chloroprocaine IT injections should not exceed 2 min. The study will include a screening phase (Visit 1, Day -21/-1), a treatment phase (IMP IT administration, anaesthesia and surgical procedure: Visit 2, Day 1) and a follow-up phase including an observation period (Visit 3), a final visit and two follow-ups (24 h post-dose and day 7±1).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pain, Postoperative

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Eligible patients will be randomised into four treatment groups (15 patients/group) to receive either one of the three single doses of Paracetamol 3% (30 mg, 60 mg, 90 mg) or placebo solution (1 mL, 2 mL, 3 mL) according to the randomised, parallel-group design.
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
The study will be double-blind. Neither the Investigator/co-investigators/study nurses involved in the clinical study procedures, nor will the patients be aware of the administered treatment. At the site, syringes for injection will then be prepared by a person not involved in any other study-related activities where a bias is possible.
Allocation
Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
30 mg Paracetamol 3% (1 mL)
Arm Type
Experimental
Arm Description
30 mg Paracetamol 3% (1 mL), solution for injection, single dose by intrathecal injection (IT)
Arm Title
60 mg Paracetamol 3% (2 mL)
Arm Type
Experimental
Arm Description
60 mg Paracetamol 3% (2 mL), solution for injection, single dose by intrathecal injection (IT)
Arm Title
90 mg Paracetamol 3% (3 mL)
Arm Type
Experimental
Arm Description
90 mg Paracetamol 3% (3 mL), solution for injection, single dose by intrathecal injection (IT)
Arm Title
Placebo, 0.9% saline solution
Arm Type
Placebo Comparator
Arm Description
Placebo, 0.9% saline solution (1 mL, 2 mL or 3 mL), solution for injection, single dose by intrathecal injection (IT)
Intervention Type
Drug
Intervention Name(s)
30 mg Paracetamol 3% (1 mL)
Intervention Description
Single administration by intrathecal injection just before spinal anaesthesia. The injection will be performed according to the hospital procedures. For the intrathecal injection of Paracetamol followed by the intrathecal injection of the anaesthetic, two needles will be used: one introducer needle, which will serve to introduce the second needle through the skin, plus one intrathecal Pencil point needle (27-G or 25-Gauge or Reganesth or Nizell needle) to which the first syringe containing Paracetamol will be attached first, followed by the second syringe with the anaesthetic. In this way only one intrathecal puncture will be performed. Lumbar puncture will be done according to the standard hospital procedures.
Intervention Type
Drug
Intervention Name(s)
60 mg Paracetamol 3% (2 mL)
Intervention Description
Single administration by intrathecal injection just before spinal anaesthesia. The injections will be performed according to the hospital procedures. For the intrathecal injection of Paracetamol followed by the intrathecal injection of the anaesthetic, two needles will be used: one introducer needle, which will serve to introduce the second needle through the skin, plus one intrathecal Pencil point needle (27-G or 25-Gauge or Reganesth or Nizell needle) to which the first syringe containing Paracetamol will be attached first, followed by the second syringe with the anaesthetic. In this way only one intrathecal puncture will be performed. Lumbar puncture will be done according to the standard hospital procedures.
Intervention Type
Drug
Intervention Name(s)
90 mg Paracetamol 3% (3 mL)
Intervention Description
Single administration by intrathecal injection just before spinal anaesthesia. The injections will be performed according to the hospital procedures. For the intrathecal injection of Paracetamol followed by the intrathecal injection of the anaesthetic, two needles will be used: one introducer needle, which will serve to introduce the second needle through the skin, plus one intrathecal Pencil point needle (27-G or 25-Gauge or Reganesth or Nizell needle) to which the first syringe containing Paracetamol will be attached first, followed by the second syringe with the anaesthetic. In this way only one intrathecal puncture will be performed. Lumbar puncture will be done according to the standard hospital procedures.
Intervention Type
Drug
Intervention Name(s)
Placebo, 0.9% saline solution
Other Intervention Name(s)
physiological solution
Intervention Description
Single administration by intrathecal injection just before spinal anaesthesia. The injections will be performed according to the hospital procedures. For the intrathecal injection of Placebo followed by the intrathecal injection of the anaesthetic, two needles will be used: one introducer needle, which will serve to introduce the second needle through the skin, plus one intrathecal Pencil point needle (27-G or 25-Gauge or Reganesth or Nizell needle) to which the first syringe containing Placebo will be attached first, followed by the second syringe with the anaesthetic. In this way only one intrathecal puncture will be performed. Lumbar puncture will be done according to the standard hospital procedures.
Intervention Type
Drug
Intervention Name(s)
NIMP: Chloroprocaine HCl 1% (10 mg/mL), solution for injection
Other Intervention Name(s)
Ampres 1%
Intervention Description
Immediately after intrathecal administration of the Paracetamol dose or Placebo, all patients will receive a single intrathecal dose of Chloroprocaine HCl 1% according to the Summary of Product Characteristics indications. Time interval between the 2 administrations should not exceed 2 min.
Primary Outcome Measure Information:
Title
Pain Intensity at Rest Evaluated Using a 0-100 mm VAS
Description
The study primary efficacy measures will be the VAS scores at each predefined time-point after the anaesthetic intrathecal injection until eligibility for home discharge ( VAS scale is 0-100 mm, where 0 is no pain and 100 is maximum pain)
Time Frame
Pain intensity at rest evaluated using a 0-100 mm VAS at baseline (within 30 min before NIMP IT injection, 0 h), 1, 1.25, 1.5, 1.75, 2 h after NIMP IT injection, then every 30 min after NIMP IT injection until eligibility for home discharge.
Secondary Outcome Measure Information:
Title
Pain at Rest AUCt1-t2
Description
AUC t1-t2 is defined as the area under the pain intensity curve at the specified time-intervals
Time Frame
Up to 4 hours after injection
Title
Pain at Rest AUClast
Description
AUClast is defined as the area under the pain intensity curve from 0 h up to the last assessment time
Time Frame
Up to 24 hours after injection
Title
Time to First Postoperative Analgesia (Level 1 or 2)
Description
Postoperatively, patients will be administered an analgesic as needed. Post-operative analgesia could include Ketorolac i.v. [Toradol] 30 mg (level 1 analgesia) and/or Tramadol i.v. 1 mg/kg (level 2 analgesia). The administered analgesic (level 1 or 2), analgesic dose and intake frequency will be decided according to the reported surgery-related pain intensity. Post-operatively, patients were administered an analgesic, as needed. Post-operative analgesia could include Ketorolac i.v. [Toradol] 30 mg (level 1 analgesia) and/or Tramadol i.v. 1 mg/kg (level 2 analgesia).
Time Frame
Up to 24 hours after surgery
Title
Partecipants to Received Level 1 Analgesia
Description
Partecipants to received Ketorolac i.v. [Toradol] 30 mg administration (level 1 analgesia)
Time Frame
from surgery day to 24 hours after surgery
Title
Partecipants Received Level 2 Analgesia
Description
Partecipants received Tramadol i.v. 1 mg/kg administration (level 2 analgesia)
Time Frame
from surgery day to 24 hours after surgery
Title
Total Number of Partecipants Receiving Analgesic 1
Description
Total number of partecipants receiving Ketorolac i.v. [Toradol] 30 mg
Time Frame
From surgery day to 24 hours after surgery
Title
Total Number of Partecipants Receiving Analgesic 2
Description
Total Number of Partecipants Receiving Tramadol i.v. 1 mg/kg
Time Frame
from surgery day to 24 hours after surgery
Title
Percentage of Patients Requiring Analgesia in the First 2 h After Surgery End
Description
Percentage of patients requiring analgesia (level 1 or level 2) in the first 2 h after surgery end
Time Frame
Form surgery day to 2 hours after surgery end
Title
Percentage of Patients Requiring Analgesia in the First 4 h After Surgery End
Description
Percentage of patients requiring analgesia (level 1 or level 2) in the first 4 h after surgery end
Time Frame
from surgery day to 4 hours after surgery end
Title
Percentage of Patients Requiring Analgesia From Surgery End Until Eligibility for Discharge
Description
Percentage of patients requiring analgesia (level 1 or level 2) from surgery end until eligibility for home discharge
Time Frame
from surgery day to 24 hours after surgery
Title
Percentage of Patients Requiring Level 1 Analgesia From Surgery End Until Eligibility for Discharge
Description
Percentage of patients requiring level 1 analgesia from surgery end until eligibility for home discharge
Time Frame
from surgery day to 24 hours after surgery
Title
Percentage of Patients Requiring Level 2 Analgesia From Surgery End Until Eligibility for Discharge
Description
Percentage of Patients Requiring Level 2 Analgesia From Surgery End Until Eligibility for Home Discharge
Time Frame
from surgery day to 24 hours after surgery
Title
Percentage of Patients Requiring Supplementary Analgesia, Other Than the Planned Level 1 or 2 Analgesia
Description
Percentage of patients requiring supplementary analgesia, other than the planned level 1 or 2 analgesia
Time Frame
from surgery day to 24 hours after surgery
Title
Percentage of Patients Requiring Rescue Anaesthesia
Description
Percentage of patients requiring rescue anaesthesia
Time Frame
from surgery day to 1 hour after injection
Title
Time to Onset of Spinal Block (i.e. Time to Readiness for Surgery)
Description
Spinal block/Readiness for surgery is defined as the presence of an adequate motor block (Bromage's score ≥ 2) and loss of Pinprick sensation, according to the Investigator's opinion. Time to readiness for surgery is defined as the time from the spinal injection (time 0 h) to achievement of readiness for surgery.
Time Frame
Up to 20 minutes after injection
Title
Maximum Sensory Block
Description
Maximum level of sensory block
Time Frame
Intraoperative
Title
Time to Sensory Block
Description
Time to maximum level of sensory block (bilateral Pinprick test using a 20-G hypodermic needle)
Time Frame
Intraoperative
Title
Time to Regression of Spinal Block
Description
Time period from spinal injection to the complete regression of sensory block to S1.
Time Frame
Up to 4 hours after injection
Title
Time to Ambulation
Description
Time to unassisted ambulation
Time Frame
Up to 24 hours after injection
Title
Time to First Urine
Description
Time to first spontaneous urine voiding
Time Frame
Up to 24 hours after injection
Title
Time to Eligibility for Discharge
Description
Time to eligibility for home discharge
Time Frame
Up to 24 hours after injection
Other Pre-specified Outcome Measures:
Title
Number of Participants With Neurological Complications Including TNS
Description
Number of Participants with Neurological Complications Including TNS at 24 h post-dose and at day 7±1
Time Frame
From anaesthetic intrathecal injection up to day 7±1 (i.e. 6±1 days after analgesic/anaesthetic IT injection and surgery)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Informed consent: signed written informed consent before inclusion in the study Sex, age and surgery: male/female patients, 18-80 years old (inclusive), scheduled for short duration (up to 40 min) knee procedures Body Mass Index (BMI): 18 - 32 kg/m2 inclusive ASA physical status: I-III Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study. Exclusion Criteria: Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study. Contraindications to spinal anaesthesia. History of neuromuscular diseases to the lower extremities ASA physical status: IV-V Further anaesthesia: patients expected to require further anaesthesia Allergy: ascertained or presumptive hypersensitivity to the active principles (paracetamol and/or ester type anaesthetics) and/or formulations' ingredients or related drugs, non-steroidal anti-inflammatory drugs and/or opioid derivatives; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers could affect the outcome of the study Chronic pain syndromes: patients with chronic pain syndromes taking opioids, anticonvulsant agents or chronic analgesic therapy Pain assessment: patients anticipated to be unable to make a reliable self-report of pain intensity Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that may interfere with the aim of the study; ascertained psychiatric and neurological diseases, sepsis, blood coagulation disorders, severe cardiopulmonary disease, thyroid disease, diabetes, other neuropathies, history or evidence of heart failure. History of severe head trauma that required hospitalisation, intracranial surgery or stroke within the previous 30 days, or any history of intracerebral arteriovenous malformation, cerebral aneurism or CNS mass lesion Medications: medication known to interfere with the extent of spinal blocks for 2 weeks before the start of the study. Paracetamol formulations, other than the investigational product, for 2 weeks before the start of the study and during the study. Hormonal contraceptives for females are allowed. Anti-hypotensive, anti-bradycardia (e.g. ephedrine, atropine, Ringer's solution), anti-haemetic and anti-nausea medications will be allowed Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval is calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study Drug, alcohol: history of drug or alcohol abuse according to the Investigator's opinion Pregnancy and lactation: positive pregnancy test at screening (if applicable), pregnant or lactating women [The pregnancy test will be performed to all fertile women and to all women up to 55 years old, if not in proven menopause (available laboratory test confirming menopause or surgically sterilised)]
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Claudio Camponovo, MD
Organizational Affiliation
Department of Anaesthesiology, Clinica Ars Medica, Via Cantonale, CH-6929 Gravesano, Switzerland
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Anaesthesiology, Clinica Ars Medica
City
Gravesano
ZIP/Postal Code
6929
Country
Switzerland

12. IPD Sharing Statement

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Intrathecal Paracetamol Before Spinal Anaesthesia With Chloroprocaine HCl 1% for Short Knee Procedures

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