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UMIN ID:

Recruitment status Completed
Unique ID issued by UMIN UMIN000033217
Receipt No. 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

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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 Anesthetic preconditioning effects of desflurane versus propofol on tourniquet induced ischemia-reperfusion injury during anterior cruciate ligament reconstruction:a single-centre randomized controlled study.
Scientific Title:Acronym Anesthetic preconditioning effects of desflurane versus propofol on lower limb surgery using tourniquet.
Region
Japan

Condition
Condition Anterior cruciate ligament injury
Classification by specialty
Orthopedics Anesthesiology
Classification by malignancy Others
Genomic information NO

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 NO
Institution consideration Institution is not considered as adjustment factor.
Blocking YES
Concealment Pseudo-randomization

Intervention
No. of arms 2
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 60

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
Institute Medical Corporation Sakai Orthopedics Fukuoka Sports Clinic
Institute
Department

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
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
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&ndash;MM(x)= CPK&ndash;MM(x)&ndash;CPK&ndash;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&ndash;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&plusmn;SD) DES: 12865.4&plusmn;8770.9(U/L&times;hr),pro:10434.3&plusmn;5117.8(U/L&times;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&ndash;sectional slice of the quadriceps femoris muscles 5cm above the upper margin of the patella:(S5)
A cross&ndash;sectional slice of the quadriceps femoris muscles 10cm above the upper margin of the patella:(S10)
A0: a cross&ndash;sectional area of the quadriceps femoris muscles traced and calculated on MRI before operation
A1: a cross&ndash;sectional area of the quadriceps femoris muscles traced and calculated on MRI on postoperative day 9 &lt;SUP&gt;th&lt;/SUP&gt;

&DELTA;A(%)=(A1&ndash;A0/A0)&times;100
Data were reviewed using Shapiro&ndash;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&ndash;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: &ndash;4.4&plusmn;9.0%, for pro group: &ndash;3.8&plusmn;8.7%, P=0.746  &DELTA;A(S10) for DES group; &ndash;4.8&plusmn;5.7%, for pro group: &ndash;2.8&plusmn;4.3%, P=0.054  
The criterion for rejection of the null hypothesis was P&lt;0.05
Bell curve for Excel &reg; 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
URL(English) https://upload.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


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