UMIN-CTR Clinical Trial

Unique ID issued by UMIN	UMIN000033217
Receipt number	R000037869
Scientific Title	Anesthetic preconditioning effects of desflurane versus propofol on tourniquet induced ischemia-reperfusion injury during anterior cruciate ligament reconstruction:a single-centre randomized controlled study.
Date of disclosure of the study information	2018/07/01
Last modified on	2019/12/23 09:23:18

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Basic information

Public title

Anesthetic preconditioning effects of desflurane versus propofol on tourniquet induced ischemia-reperfusion injury during anterior cruciate ligament reconstruction:a single-centre randomized controlled study.

Acronym

Anesthetic preconditioning effects of desflurane versus propofol on lower limb surgery using tourniquet.

Scientific Title

Scientific Title:Acronym

Anesthetic preconditioning effects of desflurane versus propofol on lower limb surgery using tourniquet.

Region

Japan

Condition

Anterior cruciate ligament injury

Classification by specialty

Orthopedics Anesthesiology

Classification by malignancy

Others

Genomic information

Objectives

Narrative objectives1

To evaluate anesthetic preconditioning effects of desflurane versus propofol on tourniquet induced ischemia-reperfusion injury during anterior cruciate ligament reconstruction,we measured blood CPK-MM and myoglobin released from damaged akeletal muscles.We hypothesized that desflurane can more effectively decrease CPK-MM and myoglobin released from damaged skeletal muscles than propofol.

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Exploratory

Trial characteristics_2

Pragmatic

Developmental phase

Assessment

Primary outcomes

Skeletal muscle cell damage quantified by the release of postoperative creatine phosphokinase-MM (CPK-MM) and the areas under the curve of the CPK-MM concentrations over the 24 h (AUC24 h) and the 48h (AUC48 h). Blood samples are taken preoperatively and 6, 12, 24, and 48 h following release of tourniquet.

Key secondary outcomes

Skeletal muscle cell damage quantified by the release of postoperative myoglobin and the areas under the curve of the myoglobin concentrations over the 24 h (AUC24 h) and the 48h (AUC48 h). Blood samples are taken preoperatively and 6, 12, 24, and 48 h following release of tourniquet.

For operative side, cross-sectional areas of quadriceps femoralis muscles were traced and calculated on MRI before operation and postoperative day 9th, at two slices of 5 cm and 10 cm above the upper margin of the patella, respectively. Change ratio of the areas at the same slice before and after operation was examined.The change ratios of patinets managed with desflurane were compared with those of patients managed with propofol at the corresponding slice, respectively.

Base

Study type

Interventional

Study design

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Single blind -participants are blinded

Control

Active

Stratification

YES

Dynamic allocation

Institution consideration

Institution is not considered as adjustment factor.

Blocking

YES

Concealment

Pseudo-randomization

Intervention

No. of arms

Purpose of intervention

Prevention

Type of intervention

Medicine

Interventions/Control_1

In patients assigned to desflurane group, following intravenous bolus injections of midazolam 1mg and remifentanil 20ug, a continuous intravenous infusion of midazolam at 0.05mg/kg/hr was maintained combined with a continuous infusion of remifentanil at 0.0167 ug/kg/min until an intrathecal anesthesia with 0.5% hyperbaric bupivacaine of 2.5 Ml combined with replacement of an epidural catheter was completed. Then the continuous infusion of midazolam was quitted after a bolus 0.5 mg injection. All patients received intravenous injection of atropine 0.3~0.5 mg before induction of general anesthesia. General anesthesia was induced with desflurane after an additional 10ug bolus injection of remifentanil. The continuous infusion of remifentanil was maintained until extubation of an airway device after surgery. A supralaryngeal airway was inserted after another bolus injection of remifentanil 10ug, at an end-tidal desflurane concentration more than 5 %. Eight % of an end-tidal desflurane concentration was achieved before inflation of the tourniquet at a pressure of 250 mmHg. Ventilation was maintained by pressure-control mode with end-tidal CO2 concentration from 30 to 40 mmHg. Inhalational gas-mixture was Air:O2=1:1. Total gas flow was maintained from 2~4 L/min. General anesthesia was maintained with the continuous infusion of remifentanil and 8 % desflurane until deflation of the tourniquet. Before end of the surgery, desflurane concentration was adjusted downwardly.
All patients received a common postoperative multimodal analgesia combined with epidural patient-controlled analgesia (EPCA) and acetoaminophen. Neither adrenocortico steroids nor non-steroidal anti-inflammatory drugs was administered in all patients until the final blood sample was taken at the postoperative day 2nd .

Interventions/Control_2

In patients assigned to propofol group, after an intravenous injection of midazolam 1mg, intravenous target-controlled infusion of propofol set at a target plasma concentration of 0.5ug/ml was maintained combined with a continuous infusion of remifentanil at 0.0167 ug/kg/min following a bolus injection of remifentanil 20ug during the intrathecal anesthesia combined with replacement of an epidural catheter. After an intravenous injection of atropine 0.3~0.5 mg, general anesthesia was induced with propofol reset at a target plasma concentration of 4ug/ml, combined with an additional 10ug bolus injection of remifentanil and the continuous infusion of remifentanil. A supralaryngeal airway was inserted after another 10ug bolus injection of remifentanil, at a propofol simulated plasma concentration of 2.5 ug/ml or more. A simulated propofol plasma concentration of 4.0 ug/ml was achieved before inflation of the tourniquet at a pressure of 250 mmHg. General anesthesia was maintained with target-controlled infusion of propofol set at a target plasma concentration of 4.0 u/ml until deflation of the tourniquet. The continuous infusion of remifentanil was maintained until extubation of an airway device after surgery. Ventilation was maintained by pressure-control mode with end-tidal CO2 30~40 mmHg. Inhalational gas-mixture was Air:O2=1:1. Total gas flow was maintained at 2-4 l/min. After deflation of the tourniquet, the target plasma concentration of propofol was adjusted downwardly.
All patients received a common postoperative multimodal analgesia combined with epidural patient-controlled analgesia (EPCA) and acetoaminophen. Neither adrenocortico steroids nor non-steroidal anti-inflammatory drugs was administered in all patients until the final blood sample was taken at the postoperative day 2nd .

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Eligibility

Age-lower limit

16 years-old <=

Age-upper limit

50 years-old >

Gender

Male and Female

Key inclusion criteria

1) Patients who are being enforced by a medical corporation Sakai Orthopedics, Fukuoka Sports Clinic for reconstructive anterior cruciate ligament (hamstring and lamina tendon transplant)
2) 16 years old and under 50
3) Any professional or amateur
4) Cases of sports enthusiast and injuries related to competition
5) Patients who received written consent (from minors in person and from substitute)

Key exclusion criteria

1) There has been a history of injury on the same side in the past
2) Cases with complex injuries
3) Patients who are predisposed to allergies to venous anesthetic propofol or volatile anesthetic desflurane
4) Patients contraindicated in regional anesthesia, difficult cases of puncture due to obesity or spinal deformity, patients who have difficulty in prescribing anesthesia and postoperative analgesia due to insufficient anesthetic effect
5) Cases in which a tourniquet pressure was required up to a pressure exceeding 250 mmHg

Target sample size

Research contact person

Name of lead principal investigator

1st name Hiroshi

Middle name

Last name Ishimura

Organization

Medical Corporation Sakai Orthopedics Fukuoka Sports Clinic

Division name

Anesthesiology

Zip code

811-1345

Address

1-13-43 Mukaishinmachi Minamiku Fukuoka city Fukuoka prefecture

TEL

092-557-8886

Email

ishimura@med-sakai.jp

Public contact

Name of contact person

1st name Tadahiro

Middle name

Last name Horiguchi

Organization

Medical Corporation Sakai Orthopedics Fukuoka Sports Clinic

Division name

Research Bureau

Zip code

811-1345

Address

1-13-43 Mukaishinmachi Minamiku Fukuoka city Fukuoka prefecture

TEL

092-557-8886

Homepage URL

Email

horiguchi@med-sakai.jp

Sponsor or person

Institute

Medical Corporation Sakai Orthopedics Fukuoka Sports Clinic

Institute

Department

Personal name

Funding Source

Organization

None

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Other related organizations

Co-sponsor

Name of secondary funder(s)

IRB Contact (For public release)

Organization

Clinical Reseach Network Fukuoka

Address

1,1,3 Maidashi,Higashi,Fukuoka,Fukuoka

Tel

092-643-7171

Email

mail@crnfukuoka.jp

Secondary IDs

YES

Study ID_1

17-E02

Org. issuing International ID_1

Clinical research network fukuoka

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

医療法人　堺整形外科医院　福岡スポーツクリニック

Other administrative information

Date of disclosure of the study information

2018 Year 07 Month 01 Day

Related information

URL releasing protocol

Publication of results

Published

Result

URL related to results and publications

Number of participants that the trial has enrolled

106

Results

On the contrary to the results obtained in cardiac surgeries, inhalational anesthetic Desflurane showed no advantageous effect over intravenous anesthetic Propofol against ischemia-reperfusion injury during anterior cruciate ligament reconstruction using a tourniquet.

Results date posted

2019 Year 12 Month 06 Day

Results Delayed

Delay expected

Results Delay Reason

Please see to the comment below, Other Related Information.

Date of the first journal publication of results

Baseline Characteristics

Participant flow

CONSORT 2010 Flow Diagram

Assessed for eligibility (n=166)
Excluded (n=60) Not meeting inclusion criteria(n=55) Declined to participate(n=3) Other reasons(n=2)
Randomized(n=106)
Propofol group(n=54) Lost to follow-up(n=3: Not available for blood sample) Analyzed(n=51)
Desflurane group(n=52) Lost to follow-up(n=3: Not available for blood sample) Analyzed(n=49)

Adverse events

Hypotension: vasopressors or sympathomimetics was(were) administered.
Bradycardia: nearly 40 bpm or less, and atropine or / and ephedrine was / were administered.
Arrhythmia: means sinus tachycardia(more than 100bpm), except for VPCs in a propofol case.
Delayed emergence: took more than 30 minutes after end of the surgery.
Emergence agitation: agitation, delirium, or excitation at emergence, described in anesthetic records.
PONV: postoperative nausea and vomiting
PHT: Postural hypotension
Dysuria : a catheter insertion required for urination.
Headache, Lumbago, Sore throat: checked by nurses at every bedside interview.

Desflurane group
Intraoperative and while staying in the operating room.
Hypotension:16/49 33%
Bradycardia: 5/49 10%
Arrythmia; 28/49 57%
Delayed emergence: 3/49 6%
Emergence agitation: 0/49 0%
PONV; 8/49 16%
Apnea after remove of the oral air way, where a mask-ventilation support was required for rescue: 1/49 2%

In the ward for three days after surgery
PONV; 18/49 37%
PHT: 14/49 29%
Dysuria : 0/49 0%
Headache: 4/49 8%, Lumbago:14/49 29%, Sore throat:12/49 24%
Extra-pyramidal syndromes: 1/49 2%

Propofol group
Intraoperative and while staying in the operating room.
Hypotension:16/51 31%
Bradycardia: 7/51 14%
Arrythmia; 5/51 10%
Delayed emergence: 6/51 12%
Emergence agitation: 0/51 0%
PONV; 0/51 0%

In the ward for three days after surgery
PONV; 5/51 10%
PHT: 11/51 22%
Dysuria : 0/51 0%
Headache: 2/51 4%, Lumbago:17/51 33%, Sore throat:15/51 29%

Outcome measures

CPK–MM(x)= CPK–MM(x)–CPK–MM(0)
(0): before induction of anesthesia
(x): x hour after deflation of the tourniquet

A line graph was drown consisting of the vertical axis(&DELTA;CPK–MM:U/L) and the horizontal axis(time after deflation of the tourniquet: hr).Then the area under the line was calculated.The results were indicated as (mean±SD) DES: 12865.4±8770.9(U/L×hr),pro:10434.3±5117.8(U/L×hr) Based on the ROC obtained from the data, AUC was calculated(AUC=0.57).

In the same way as above, AUC for Mb was also calculated (AUC=0.55)

A cross–sectional slice of the quadriceps femoris muscles 5cm above the upper margin of the patella:(S5)
A cross–sectional slice of the quadriceps femoris muscles 10cm above the upper margin of the patella:(S10)
A0: a cross–sectional area of the quadriceps femoris muscles traced and calculated on MRI before operation
A1: a cross–sectional area of the quadriceps femoris muscles traced and calculated on MRI on postoperative day 9 <SUP>th</SUP>

&DELTA;A(%)=(A1–A0/A0)×100
Data were reviewed using Shapiro–Wilk test, which showed as followed: &DELTA;A(S5) for DES group was P=0.81, for pro group was P=0.56 and &DELTA;A(S10) for DES group was P=0.17, for pro group was P=0.85, indicating the data followed normal distribution.Data were reviewed using Shapiro–Wilk test, which showed as followed: &DELTA;A(S5) for DES group was P=0.81, for pro group was P=0.56 and &DELTA;A(S10) for DES group was P=0.17, for pro group was P=0.85, indicating the data followed normal distribution.The results were as followed; &DELTA;A(S5) for DES group: –4.4±9.0%, for pro group: –3.8±8.7%, P=0.746 &DELTA;A(S10) for DES group; –4.8±5.7%, for pro group: –2.8±4.3%, P=0.054
The criterion for rejection of the null hypothesis was P<0.05
Bell curve for Excel ® was used for statistical analysis.

Plan to share IPD

IPD sharing Plan description

Progress

Recruitment status

Completed

Date of protocol fixation

2017 Year 10 Month 27 Day

Date of IRB

2017 Year 08 Month 28 Day

Anticipated trial start date

2017 Year 11 Month 05 Day

Last follow-up date

2019 Year 03 Month 03 Day

Date of closure to data entry

2019 Year 03 Month 03 Day

Date trial data considered complete

2019 Year 03 Month 03 Day

Date analysis concluded

Other

Other related information

For details, please see the comments in Japanese in the left side. Comments in English is going to be prepared, so please wait for some period.

Management information

Registered date

2018 Year 06 Month 30 Day

Last modified on

2019 Year 12 Month 23 Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000037869

Research Plan
Registered date	File name
2018/09/20	研究計画書　UIMN登録版.pdf

Research case data specifications
Registered date	File name

Research case data
Registered date	File name