Clinical Trial Results:
Determination of the minimal alveolar concentration of Sevoflurane in patient with end stage liver disease
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Summary
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EudraCT number |
2014-001552-29 |
Trial protocol |
AT |
Global end of trial date |
22 Apr 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Mar 2022
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First version publication date |
01 Mar 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
1271/2014
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Medical University of Vienna
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Sponsor organisation address |
Währinger Gürtel 18-20, Vienn, Austria, 1090
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Public contact |
Sekretariat, Medizinische Universität Wien, Abteilung für Anästhesie und allgemeine Intensivmedizin, 0043 1404004102,
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Scientific contact |
Sekretariat, Medizinische Universität Wien, Abteilung für Anästhesie und allgemeine Intensivmedizin, 0043 1404004102,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
22 Apr 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
22 Apr 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Apr 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
to determine whether patients with end stage liver disease undergoing liver transplantation have lower MAC values of sevoflurane than healthy patients.
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Protection of trial subjects |
Before skin incision, acceleromyography was used to
exclude residual pharmacological paralysis. The MAC of
sevo!urane was determined by observing the patients’
motor response to initial surgical skin incision. The motor
response to skin incision was classi"ed as “response” or “no
response.” Investigators blinded to the actual ET sevoflurane
concentration observed movements of patients’ head,
arms, or legs. The response was identi"ed as “response”
when a gross, purposeful movement of the head or at least
one extremity occurred within 1 minute after skin incision.
Coughing, bucking, and straining were not noted as
movement.
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Background therapy |
- | ||
Evidence for comparator |
The potency of volatile anesthetics is expressed by the minimum alveolar concentration (MAC). A MAC of 1 is de"ned as the end-tidal (ET) alveolar concentration of the volatile anesthetic at 1 atmosphere, at which 50% of individuals do not move after initial skin incision.2 Maintaining ET alveolar concentrations of volatile anesthetics above 0.7 MAC during surgery is thought to decrease the incidence of awareness.3 In contrast, anesthesia with volatile anesthetics using a MAC greater than 1.25 might lead to side effects including bradycardia, hypotension, or accumulation of toxic degradation products.4,5 The MAC of sevo!urane has been extensively characterized in healthy adults, with values ranging from 1.7% ± 0.2%6 to 2.1% ± 0.1%7 but has not been assessed in patients with ESLD undergoing OLT. We hypothesized that the MAC of sevo!urane would be lower in patients with ESLD undergoing OLT than in patients with normal liver function undergoing major abdominal surgery. | ||
Actual start date of recruitment |
03 Aug 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 40
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Worldwide total number of subjects |
40
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EEA total number of subjects |
40
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
40
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients between 30 and 65 years of age were enrolled in the study. The study group included patients with ESLD scheduled for OLT, whereas the control group included patients without evident liver disease undergoing major abdominal surgery requiring a laparotomy with a skin incision of at least 10 cm. | |||||||||
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Pre-assignment
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Screening details |
In patients undergoing OLT, blood ammonia concentrations and the model for endstage liver disease (MELD) score were assessed on the day of transplantation. Blood gases, the acid-base status, and electrolyte concentrations were analyzed after induction of anesthesia in all patients. | |||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | |||||||||
Roles blinded |
Investigator [1] | |||||||||
Blinding implementation details |
In this prospective, blinded study, we
compared the MAC of sevoflurane among patients with ESLD undergoing OLT and patients with
normal liver function undergoing major abdominal surgery.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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ESLD scheduled for OLT | |||||||||
Arm description |
In this prospective, blinded study, we compared the MAC of sevoflurane among patients with ESLD undergoing OLT | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Sevoflurane
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection/infusion
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Routes of administration |
Injection
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Dosage and administration details |
Stable ET concentrations of sevofurane were reached 17
minutes (95% CI, 15–19) after initiating administration of
sevoflurane in all patients (Figure&1). Steady ET concentrations
of sevo!urane were maintained for 41 minutes (95%
CI, 37–45) in the OLT group and for 27 minutes (95% CI,
22–32) in the control group before skin incision.
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Arm title
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normal liver function | |||||||||
Arm description |
By including 20 patients in each group, we obtained 7 crossovers in the OLT group and 8 crossovers in the control group. The MAC of sevoflurane in patients with ESLD undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In comparison, the MAC of sevoflurane in patients with normal liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B). The relative reduction of the MAC in patients undergoing OLT was 26% (95% CI, 14–39) compared to patients with preserved liver function. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Sevoflurane
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection/infusion
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Routes of administration |
Injection
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Dosage and administration details |
Stable ET concentrations of sevofurane were reached 17
minutes (95% CI, 15–19) after initiating administration of
sevo!urane in all patients (Figure&1). Steady ET concentrations
of sevoflurane were maintained for 41 minutes (95%
CI, 37–45) in the OLT group and for 27 minutes (95% CI,
22–32) in the control group before skin incision.
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| Notes [1] - The roles blinded appear inconsistent with a simple blinded trial. Justification: This study was performed as a monocentric, single-blinded, prospective clinical trial at the Medical University of Vienna in accordance with the ethical standards stated in the Declaration of Helsinki. |
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial (overall period)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
undergoing OLT 3 minutes before
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14–39) compared to patients with
preserved liver function.
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Subject analysis set title |
Control normal liver function 3 minutes before
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14–39) compared to patients with
preserved liver function.
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Subject analysis set title |
undergoing OLT 1 minutes before
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14–39) compared to patients with
preserved liver function.
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Subject analysis set title |
Control normal liver function 1 minutes before
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14–39) compared to patients with
preserved liver function.
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Subject analysis set title |
undergoing OLT 1 minute after skin incision
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14–39) compared to patients with
preserved liver function.
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Subject analysis set title |
Control normal liver function 1minute after skin incision
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14
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End points reporting groups
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Reporting group title |
ESLD scheduled for OLT
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Reporting group description |
In this prospective, blinded study, we compared the MAC of sevoflurane among patients with ESLD undergoing OLT | ||
Reporting group title |
normal liver function
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Reporting group description |
By including 20 patients in each group, we obtained 7 crossovers in the OLT group and 8 crossovers in the control group. The MAC of sevoflurane in patients with ESLD undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In comparison, the MAC of sevoflurane in patients with normal liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B). The relative reduction of the MAC in patients undergoing OLT was 26% (95% CI, 14–39) compared to patients with preserved liver function. | ||
Subject analysis set title |
undergoing OLT 3 minutes before
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14–39) compared to patients with
preserved liver function.
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Subject analysis set title |
Control normal liver function 3 minutes before
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14–39) compared to patients with
preserved liver function.
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Subject analysis set title |
undergoing OLT 1 minutes before
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14–39) compared to patients with
preserved liver function.
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Subject analysis set title |
Control normal liver function 1 minutes before
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14–39) compared to patients with
preserved liver function.
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Subject analysis set title |
undergoing OLT 1 minute after skin incision
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14–39) compared to patients with
preserved liver function.
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Subject analysis set title |
Control normal liver function 1minute after skin incision
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
By including 20 patients in each group, we obtained 7
crossovers in the OLT group and 8 crossovers in the control
group. The MAC of sevoflurane in patients with ESLD
undergoing OLT was 1.3% (95% CI, 1.1–1.4; Figure&2A). In
comparison, the MAC of sevoflurane in patients with normal
liver function was 1.7% (95% CI, 1.6–1.9; Figure& 2B).
The relative reduction of the MAC in patients undergoing
OLT was 26% (95% CI, 14
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End point title |
Patients with ESLD and with normal liver function | ||||||||||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
3 minute before; 1 minute before; 1 minute after skin incision
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Statistical analysis title |
Primary | ||||||||||||||||||||||||||||
Comparison groups |
undergoing OLT 3 minutes before v Control normal liver function 3 minutes before v undergoing OLT 1 minutes before v Control normal liver function 1 minutes before v undergoing OLT 1 minute after skin incision v Control normal liver function 1minute after skin incision
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Number of subjects included in analysis |
45
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Analysis specification |
Post-hoc
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Analysis type |
other [1] | ||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||
Method |
Dixon up-and-down” method. | ||||||||||||||||||||||||||||
Confidence interval |
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| Notes [1] - Dixon up-and-down” method. |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Patients undergo standard electrocardiography, pulse oximetry, arterial
blood pressure, capnography, nasopharyngeal temperature, and Bispectral
Index . The
body temperature between 35.5 and 37°C)
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||
Dictionary version |
20.0
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| Frequency threshold for reporting non-serious adverse events: 5% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: There are no non serious adverse events |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/28678075 |
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