Clinical Trial Results:
Optimal cerebral perfusion after an extracranial-intracranial bypass: should we increase blood pressure or cardiac output?
|
Summary
|
|
EudraCT number |
2018-002008-15 |
Trial protocol |
NL |
Global end of trial date |
22 Jul 2019
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
06 Aug 2020
|
First version publication date |
06 Aug 2020
|
Other versions |
|
Summary report(s) |
Summary of results |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
NL65095.041.18
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Netherlands Trial Register: NL7077 | ||
|
Sponsors
|
|||
Sponsor organisation name |
University Medical Center Utrecht
|
||
Sponsor organisation address |
Heidelberglaan , Utrecht, Netherlands, 3584 CX
|
||
Public contact |
Research office DVF, University Medical Center Utrecht, 0031 0887577081,
|
||
Scientific contact |
Research office DVF, University Medical Center Utrecht, 0031 0887577081, a.akkermans@umcutrecht.nl
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
01 Apr 2020
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
22 Jul 2019
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
22 Jul 2019
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
In this pilot study, we aim to determine the mean change in graft perfusion when increasing the cardiac output and the mean change in graft perfusion when increasing the blood pressure, to enable further research to establish We aim to study whether an increase in cardiac output results in a higher graft perfusion than an increase in blood pressure in patients undergoing cerebral revascularization surgery with a bypass.
|
||
Protection of trial subjects |
Patients were informed prior to participation in the trial. Strict in- and exclusion criteria were defined. Exclusion criteria were an emergency procedure, pregnancy, a contra-indication for either dobutamine or phenylephrine, and a mean arterial pressure (MAP) <60 mmHg or SBP >180 mmHg under general anaesthesia before start of the interventions.
|
||
Background therapy |
General anesthesia with phenylephrine to reach appropriate intra-operative blood pressure levels. The intervention (dobutamine to increase cardiac output and phenylephrine to increase blood pressure) was used on top of this. | ||
Evidence for comparator |
We hypothesized that inotropes – to increase cardiac output - rather than vasopressors – to increase blood pressure – are a key element for adequate graft flow and cerebral perfusion, based on the Hagen–Poiseuille equation | ||
Actual start date of recruitment |
03 Sep 2018
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Netherlands: 10
|
||
Worldwide total number of subjects |
10
|
||
EEA total number of subjects |
10
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
10
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
|||||||||||
|
Recruitment
|
|||||||||||
Recruitment details |
This randomized crossover study was conducted between September 2018 and July 2019 at the University Medical Centre (UMC) Utrecht Adult patients (18 years or above) presenting for an extracranial-intracranial or intracranial-intracranial cerebral bypass were eligible for inclusion after written informed consent. | ||||||||||
|
Pre-assignment
|
|||||||||||
Screening details |
Inclusion: ECIC bypass. Exclusion: emergency procedure, pregnancy, a contra-indication dobutamine or phenylephrine, and a mean arterial pressure (MAP) <60 mmHg or Systolic blood pressuBP >180 mmHg under general anaesthesia. 15 patients presented for 17 procedures, 8 were included for 10 procedures (two patients presented twice). Wash out: 20 minute | ||||||||||
|
Pre-assignment period milestones
|
|||||||||||
Number of subjects started |
10 | ||||||||||
Intermediate milestone: Number of subjects |
start of study intervention: 10
|
||||||||||
Number of subjects completed |
10 | ||||||||||
|
Period 1
|
|||||||||||
Period 1 title |
Baseline
|
||||||||||
Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Randomised - controlled
|
||||||||||
Blinding used |
Single blind [1] | ||||||||||
Roles blinded |
Subject, Monitor, Carer | ||||||||||
Blinding implementation details |
See period 1 (intervention 1)
|
||||||||||
|
Arms
|
|||||||||||
|
Arm title
|
Baseline | ||||||||||
Arm description |
Before start dobutamine or phenylephrine, patients were allowed to use phenylephrine infusion prior to start of the study. | ||||||||||
Arm type |
cross over - dobutamine first | ||||||||||
Investigational medicinal product name |
Phenylephrine
|
||||||||||
Investigational medicinal product code |
SUB09788MIG
|
||||||||||
Other name |
|||||||||||
Pharmaceutical forms |
Infusion
|
||||||||||
Routes of administration |
Intravenous drip use
|
||||||||||
Dosage and administration details |
phenylephrine 0.15-1 µg kg-1 min-1 for 6-23 minutes (depending on effect) via central venous catheter
|
||||||||||
| Notes [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial. Justification: The investigator and analysis were not blind, but the patient was blinded, as well the anaesthesiologist for graft flow, whereas the neurosurgeon, who measured graft flow, was blinded for medication given and blood pressure and cardiac index data. |
|||||||||||
|
|||||||||||
|
Period 2
|
|||||||||||
Period 2 title |
Intervention: phenylephrine (cross over)
|
||||||||||
Is this the baseline period? |
No | ||||||||||
Allocation method |
Randomised - controlled
|
||||||||||
Blinding used |
Single blind [2] | ||||||||||
Roles blinded |
Subject, Monitor, Carer | ||||||||||
Blinding implementation details |
The anaesthesiologist was blinded for graft flow, whereas the neurosurgeon, who measured graft flow, was blinded for medication given and blood pressure and cardiac index data.
|
||||||||||
|
Arms
|
|||||||||||
|
Arm title
|
Phenylephrine | ||||||||||
Arm description |
The interventions took place after construction of the bypass. Patients were randomized to sequentially receive dobutamine and phenylephrine via a central venous catheter. After a first reference phase to record baseline graft flow, the first intervention (administration of dobutamine or phenylephrine) was applied. After a wash-out period of twenty minutes and a second reference phase, the alternative intervention was applied. The dosages of dobutamine (2-15 µg kg-1 min-1) and phenylephrine (0.15-1 µg kg-1 min-1) varied depending on their effect on cardiac index and blood pressure, respectively. For dobutamine, the infusion rate was targeted at an increase in cardiac index of at least 10%, as compared to the mean cardiac index in the reference phase. For phenylephrine, the infusion rate was adjusted to target a 10% increase in MAP as compared to the reference phase. During the reference and the intervention phases SBP, MAP, heart rate, stroke volume, cardiac index and graft | ||||||||||
Arm type |
Active comparator | ||||||||||
Investigational medicinal product name |
Phenylephrine
|
||||||||||
Investigational medicinal product code |
SUB09788MIG
|
||||||||||
Other name |
|||||||||||
Pharmaceutical forms |
Infusion
|
||||||||||
Routes of administration |
Intravenous drip use
|
||||||||||
Dosage and administration details |
phenylephrine 0.15-1 µg kg-1 min-1 for 6-23 minutes (depending on effect) via central venous catheter
|
||||||||||
| Notes [2] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial. Justification: The investigator and analysis were not blind, but the patient was blinded, as well the anaesthesiologist for graft flow, whereas the neurosurgeon, who measured graft flow, was blinded for medication given and blood pressure and cardiac index data. |
|||||||||||
|
|||||||||||
|
Period 3
|
|||||||||||
Period 3 title |
Intervention: dobutamine (cross over)
|
||||||||||
Is this the baseline period? |
No | ||||||||||
Allocation method |
Randomised - controlled
|
||||||||||
Blinding used |
Single blind [3] | ||||||||||
Roles blinded |
Subject, Monitor, Carer | ||||||||||
Blinding implementation details |
The anaesthesiologist was blinded for graft flow, whereas the neurosurgeon, who measured graft flow, was blinded for medication given and blood pressure and cardiac index data.
|
||||||||||
|
Arms
|
|||||||||||
|
Arm title
|
Dobutamine (cross over) | ||||||||||
Arm description |
The interventions took place after construction of the bypass. Patients were randomized to sequentially receive dobutamine and phenylephrine via a central venous catheter. After a first reference phase to record baseline graft flow, the first intervention (administration of dobutamine or phenylephrine) was applied. After a wash-out period of twenty minutes and a second reference phase, the alternative intervention was applied. The dosages of dobutamine (2-15 µg kg-1 min-1) and phenylephrine (0.15-1 µg kg-1 min-1) varied depending on their effect on cardiac index and blood pressure, respectively. For dobutamine, the infusion rate was targeted at an increase in cardiac index of at least 10%, as compared to the mean cardiac index in the reference phase. For phenylephrine, the infusion rate was adjusted to target a 10% increase in MAP as compared to the reference phase. During the reference and the intervention phases SBP, MAP, heart rate, stroke volume, cardiac index and graft | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Dobutamine hydrochloride
|
||||||||||
Investigational medicinal product code |
SUB01803MIG
|
||||||||||
Other name |
|||||||||||
Pharmaceutical forms |
Infusion
|
||||||||||
Routes of administration |
Intravenous drip use
|
||||||||||
Dosage and administration details |
Dobutamine 2-15 µg kg-1 min-1 for 8-31 minuets (depending on effect) via central venous catheter
|
||||||||||
| Notes [3] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial. Justification: The investigator and analysis were not blind, but the patient was blinded, as well the anaesthesiologist for graft flow, whereas the neurosurgeon, who measured graft flow, was blinded for medication given and blood pressure and cardiac index data. |
|||||||||||
|
|||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Baseline
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Subject analysis sets
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set title |
Full analysis
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set type |
Full analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All ten patients were included for analysis. Only the results from dobutamine stage in one patient were excluded from the analysis since this patient developed an arrhythmia, making cardiac output measurements no longer reliable.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Baseline
|
||
Reporting group description |
Before start dobutamine or phenylephrine, patients were allowed to use phenylephrine infusion prior to start of the study. | ||
Reporting group title |
Phenylephrine
|
||
Reporting group description |
The interventions took place after construction of the bypass. Patients were randomized to sequentially receive dobutamine and phenylephrine via a central venous catheter. After a first reference phase to record baseline graft flow, the first intervention (administration of dobutamine or phenylephrine) was applied. After a wash-out period of twenty minutes and a second reference phase, the alternative intervention was applied. The dosages of dobutamine (2-15 µg kg-1 min-1) and phenylephrine (0.15-1 µg kg-1 min-1) varied depending on their effect on cardiac index and blood pressure, respectively. For dobutamine, the infusion rate was targeted at an increase in cardiac index of at least 10%, as compared to the mean cardiac index in the reference phase. For phenylephrine, the infusion rate was adjusted to target a 10% increase in MAP as compared to the reference phase. During the reference and the intervention phases SBP, MAP, heart rate, stroke volume, cardiac index and graft | ||
Reporting group title |
Dobutamine (cross over)
|
||
Reporting group description |
The interventions took place after construction of the bypass. Patients were randomized to sequentially receive dobutamine and phenylephrine via a central venous catheter. After a first reference phase to record baseline graft flow, the first intervention (administration of dobutamine or phenylephrine) was applied. After a wash-out period of twenty minutes and a second reference phase, the alternative intervention was applied. The dosages of dobutamine (2-15 µg kg-1 min-1) and phenylephrine (0.15-1 µg kg-1 min-1) varied depending on their effect on cardiac index and blood pressure, respectively. For dobutamine, the infusion rate was targeted at an increase in cardiac index of at least 10%, as compared to the mean cardiac index in the reference phase. For phenylephrine, the infusion rate was adjusted to target a 10% increase in MAP as compared to the reference phase. During the reference and the intervention phases SBP, MAP, heart rate, stroke volume, cardiac index and graft | ||
Subject analysis set title |
Full analysis
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All ten patients were included for analysis. Only the results from dobutamine stage in one patient were excluded from the analysis since this patient developed an arrhythmia, making cardiac output measurements no longer reliable.
|
||
|
|||||||||||||||||
End point title |
Graft flow | ||||||||||||||||
End point description |
Graft flow was measured with an ultrasonographic flow meter (Transonic Systems Inc., Ithaca, New York, USA), with a probe encircling the bypass in close proximity to the anastomosis with the intracranial artery. The mean graft flow was estimated for each reference and intervention phase and was plotted over time for each patient. The change in graft flow between intervention phase I and the corresponding reference phase I, and between intervention phase II and reference phase II was calculated. Afterwards, a two-sided Wilcoxon signed rank test was used to assess the difference in flow, after confirmation that the data was not normally distributed
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Difference between first and second intervention
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Analysis | ||||||||||||||||
Statistical analysis description |
The mean graft flow was estimated for each reference and intervention phase and was plotted over time for each patient. The change in graft flow between intervention phase I and the corresponding reference phase I, and between intervention phase II and reference phase II was calculated. Afterwards, a two-sided Wilcoxon signed rank test was used to assess the difference in flow, after confirmation that the data was not normally distributed. A pseudo median was reported.
|
||||||||||||||||
Comparison groups |
Dobutamine (cross over) v Phenylephrine
|
||||||||||||||||
Number of subjects included in analysis |
19
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [1] | ||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
| Notes [1] - Mean graft flow was estimated for each reference and intervention phase and was plotted over time. Change in flow between intervention phase I and reference phase I, and between intervention II and reference II was calculated. A two-sided Wilcoxon signed rank test was used to assess the difference in flow. A pseudomedian was reported. The same was done for secondary endpoints. A random multivariable linear effect model was constructed to assess treatment and carry over effect. |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary endpoint mean arterial blood pressure | ||||||||||||||||
End point description |
The change in blood pressure between intervention phase I and the corresponding reference phase I, and between intervention phase II and reference phase II was calculated. Afterwards, a two-sided Wilcoxon signed rank test was used to assess the difference in blood pressure, after confirmation that the data was not normally distributed
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Difference between two interventions
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary endpoint systolic blood pressure | ||||||||||||||||
End point description |
The change in blood pressure between intervention phase I and the corresponding reference phase I, and between intervention phase II and reference phase II was calculated. Afterwards, a two-sided Wilcoxon signed rank test was used to assess the difference in blood pressure, after confirmation that the data was not normally distributed
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Difference between two interventions
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary endpoint Cardiac output | ||||||||||||||||
End point description |
The change in cardiac output between intervention phase I and the corresponding reference phase I, and between intervention phase II and reference phase II was calculated. Afterwards, a two-sided Wilcoxon signed rank test was used to assess the difference in cardiac output after confirmation that the data was not normally distributed
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Difference between two interventions
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary endpoint heart rate | ||||||||||||||||
End point description |
The change in heart rate between intervention phase I and the corresponding reference phase I, and between intervention phase II and reference phase II was calculated. Afterwards, a two-sided Wilcoxon signed rank test was used to assess the difference in heart rate , after confirmation that the data was not normally distributed
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Difference between two interventions
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Secondary endpoint stroke volume | ||||||||||||||||
End point description |
The change in stroke volume between intervention phase I and the corresponding reference phase I, and between intervention phase II and reference phase II was calculated. Afterwards, a two-sided Wilcoxon signed rank test was used to assess the difference in stroke volume, after confirmation that the data was not normally distributed
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Difference between two interventions
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
|
Adverse events information
|
|||||||||||||||||
Timeframe for reporting adverse events |
Until end of bypass procedure
|
||||||||||||||||
Adverse event reporting additional description |
Short follow-up due to fast washout of both dobutamine and phenylephrine
|
||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||
Dictionary version |
20.1
|
||||||||||||||||
|
Reporting groups
|
|||||||||||||||||
Reporting group title |
Baseline
|
||||||||||||||||
Reporting group description |
Before start dobutamine or phenylephrine | ||||||||||||||||
|
|||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||
|
|||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Data for one patient receiving dobutamine were not included in analysis due to unreliable cardiac output values caused by arrhythmia, results during phenylephrine phase were used for this patients. | |||
