Clinical trial NCT04194151
Conditions: Propofol Adverse Reaction Anesthesia
Keywords: propofol synergy fentanyl anesthesia induction
Sponsor: Hospital Central de la Defensa Gómez Ulla
Start date: 2017-11-01; Completion date: 2018-10-26
Enrollment: 192 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Objective: Determine if, by reducing the dose of propofol and increasing the time elapsed between fentanyl and propofol administration, hemodynamic response is improved.

Methods: Patients were randomized into time groups (2 and 1 minute) and each subdivided into dose groups (1, 1.5 and 2 mg kg-1) obtaining six time-dose groups. After receiving 2 μg kg-1 of fentanyl, propofol was administered after the predetermined time. Time to hypnosis (BIS\<60) and hemodynamic parameters at pre-induction, pre-intubation and postintubation were registered.

Detailed description:
A minimum of 162 patients were required, considering an expected Mean Difference of 5 with expected Standard Deviation of 22, confidence level of 95% and power of 80%. Estimating a possible loss of 15%, it was raised to 192. Consecutive identification numbers were assigned and the sample was randomized in six groups of 32 patients according to time and dose of propofol.

Pre-oxygenation was performed until the expired oxygen fraction exceeded 80% and 2 µg/kg of intravenous fentanyl were administered. Depending on the study group, 1 or 2 minutes were allowed to pass and 1, 1.5 or 2 mg/kg of propofol were supplied (prior administration of intravenous lidocaine 0.5 mg/kg). The time in which the BIS dropped below 60 was recorded. If it did not reach that level after two minutes or when it exceeded it but then rose above 60 again, an extra dose of propofol of 0.5 mg/kg was administered. Muscle relaxation was performed with rocuronium 0.6 mg/kg. The patient was manually ventilated until endotracheal intubation was performed by the same experienced anaesthesiologist and connected to mechanical ventilation.

Data were collected manually. Statistical analysis was performed using SPSS ver. 22. Inferential statistics were performed using t-test for quantitative variables, chi-square for qualitative and ANOVA for qualitative and quantitative comparisons. Non-parametric statistical tests were used when necessary. Confidence intervals were estimated at a level of 95% and a P value of \<.05 was considered statistically significant.

Arms: arm 1: 2 mcg/kg of fentanyl administrated intravenously. wait for 2 minutes to inject 2 mg/kg of propofol arm 2: 2 mcg/kg of fentanyl administrated intravenously. wait for 2 minutes to inject 1,5 mg/kg of propofol arm 3: 2 mcg/kg of fentanyl administrated intravenously. wait for 2 minutes to inject 1 mg/kg of propofol arm 4: 2 mcg/kg of fentanyl administrated intravenously. wait for 1 minute to inject 2 mg/kg of propofol arm 5: 2 mcg/kg of fentanyl administrated intravenously. wait for 1 minute to inject 1,5 mg/kg of propofol arm 6: 2 mcg/kg of fentanyl administrated intravenously. wait for 1 minute to inject 1 mg/kg of propofol
Interventions: intervention 1: Propofol Injection
Intervention descriptions: intervention 1: 1, 1.5 or 2 mg/kg of propofol according to the subgroup

Protocol documents:
Prot_SAP_001.pdf: 
Impact of Propofol Dose Reduction in Relation to the 
Time Since Administration of Fentanyl During Anesthesia 
Induction  
  
NCT number: 04194151  
  
July 27th, 2020  
 
 


STUDY PROTOCOL 
Study center: 
Hospital Central de la Defensa “Gómez Ulla” 
Researchers data: 
Ms. Paula Agostina Vullo, Anesthesiologist. Department of Anesthesiology, 
Resuscitation and Pain Therapeutics. Hospital Central de la Defensa “Gómez Ulla”. 
Expected duration of the project: 
Approximately three years depending on the number of patients who meet inclusion 
criteria. 
Hypothesis: 
The dose of propofol necessary to reach an optimal anesthetic depth could be reduced 
if the time since the administration of fentanyl is prolonged, thus avoiding the pre-
intubation hypotension and postintubation hypertension. 
Objectives: 
General 
To determine if, by increasing the time elapsed between the administration of fentanyl 
and propofol and decreasing the dose of the latter, fewer hemodynamic changes related 
to orotracheal intubation occur. 
Specifics 
• Assess whether the patient's age is a determining factor in hemodynamic variations 
dependent on time-dose. 
• Evaluate hemodynamic variations after anesthetic induction according to the dose of 
propofol and the time since administration of fentanyl. 
• Determine if hypertensive patients and those treated with antihypertensives or heart 
rate regulating drugs suffer greater hemodynamic variations during anesthetic 
induction. 
• Analyze if the time is delayed from the administration of fentanyl delays the moment 
until reaching the optimal anesthetic depth. 
• Determine if premedication with benzodiazepines alters the time to reach hypnosis. 
Subjects and Methods 


Subjects 
All adult patients scheduled for surgery that, under the care of the same 
anesthesiologist, require general anesthesia with tracheal intubation, that meet 
inclusion criteria and accept participation and sign written consent. 
• Inclusion criteria: 
− Older than 18 years 
− Requiring general anesthesia with tracheal intubation 
− Same operator 
− Accepting participation and signing written consent 
• Exclusion criteria 
− Cardiac surgery 
− Hemodynamic instable patients: systolic blood pressure (SBP) ≤ 90 mmHg with 
clinical signs of low cardiac output (impaired state of consciousness, diuresis <0.5 
ml/kg/h, central venous saturation <60% with normal arterial saturation or 
lactate >3 mmol/l). 
− Increased risk of bronchoaspiration: absence of fasting for 6 hours for solid foods 
and 2 hours for clear liquids or presence of pathologies that imply an absence of 
gastric emptying. 
− Predictors, known or unexpected difficult airway. 
− Airway management with other supraglottic devices. 
− Known allergy to anesthetic drugs (muscle relaxants, hypnotics, etc.), egg or soy 
proteins. 
Methods 
Design 
This is a prospective and randomized clinical trial. Estimating a possible loss of 15%, 192 
patients are recruited. They will be distributed in two time-groups (2 and 1 minute) and 
in three propofol dose-subgroups (2, 1.5 and 1 mg/kg) as seen in table 1. The distribution 
in groups is done with a computerized randomizer that assigns each patient (1-192) to 
each group. Data collection begins consecutively until the sample size is reached. 
Table 1. Study groups 
Group 
Time to propofol (min) 
Propofol dose (mg/kg) 
1 
2 
2 
2 
1.5 
3 
1 
4 
1 
2 


5 
1.5 
6 
1 
 
Action protocol 
On the day of the surgery, it is verified that the patient accepted the participation and 
has signed the informed consent. Confirmation of suspension or administration of usual 
medication indicated in the preoperative evaluation is performed. 
The patient is monitored with a 5-lead electrocardiogram, pulse oximetry, non-invasive 
blood pressure cuff to the Dräger Infinity Delta monitor and Bispectral Index (BIS) 
monitor (Covidien Complete Monitor System P/N 185-0151, 2016, USA). 
In case the patient don´t have a venous access previously channeled, a peripheral 
variable-gauge venous cannula is placed according to the type of intervention (22-18 
gauge). 
Without prior fluid loading, but with a perfusion of 0.9% physiological solution at 100 
ml/h, pre-oxygenation is carried out through a facial mask with 100% O2 until the 
expired fraction of O2 in the respirator gas analyzer (Dräger Primus, Germany) exceeds 
80%. Once this point is reached, fentanyl 2 µg/kg is administered intravenously and, 
depending on the group to which the individual belonged (1, 2 and 3 or 4, 5 and 6), 
hypnotic is given after 1 or 2 minutes. 
According to the corresponding group, 1, 1.5 or 2 mg/kg of propofol are administered, 
with intravenous lidocaine 0.5 mg/kg, and the time elapsed until the BIS drop below 60 
is determined. When BIS does not reach the level of hypnosis after 2 minutes an extra 
dose of 0.5 mg/kg of propofol is administered. Subsequently, rocuronium 0.6 mg/kg is 
given and patient is maintained with manual ventilation until orotracheal intubation 
(Mackintosh # 3-4 laryngoscope). 
In the case of hypotension: SBP <90 mmHg, SBP fall >30% or mean blood pressure (MBP) 
<60 mmHg; vasoactive drugs (VAD) (ephedrine or phenylephrine equivalent doses) are 
administered. In the presence of bradycardia (heart rate -HR- fall >30% or HR <50 bpm), 
atropine 0.1 mg/kg is administered intravenously. 
Data collection and study variables 
Data is collected manually, recording patient's identification number (1-192), age, sex, 
weight, ASA, antihypertensives or beta-blockers or calcium channels previous 
treatment. The hemodynamic parameters (SBP and HR) are established as follows: 
baseline value (SBPb and HRb) is recorded before administration of fentanyl, 
preintubation value (SBP1 and HR1) is noted after the administration of propofol and 
once BIS has dropped from 60 and, finally, post-intubation value (SBP2 and HR2) is 


recorded 15 seconds after placement of the endotracheal tube. Baseline BIS values, time 
(seconds) it takes BIS to fall below 60, requirement of extra dose of hypnotic or VAD are 
also registered. Baseline, preintubation and post-intubation MBP (MBPb, MBP1 and 
MBP2 respectively) are calculated using the formula MBP = (SBP + 2DBP)/3. 
Statistical methods 
Statistical analysis is performed using the Statistical Package for Social Sciences program 
(IBM SPSS Inc., USA) version 22 for Windows. For the descriptive statistics, central 
tendency and dispersion indices were used for the qualitative and quantitative variables. 
Confidence intervals were estimated with a 95% confidence level. 
Age, weight, BIS, time at BIS less than 60, blood pressure, HR and reduction percentages 
of the BP and HR are treated as continuous quantitative variables. The remaining 
variables, such as sex, ASA risk (low: I and II – high: III and IV), antihypertensives, beta 
blockers or calcium blockers treatment, VAD and extra dose of propofol requirements 
are considered dichotomous quantitative variables. Study groups and age groups are 
classified as categorical variables.  
For inferential statistics, normality is evaluated with Kolmogorov-Smirnov test and, in 
case of normal distribution, the results are expressed as arithmetic mean (x̅) and 
standard deviation (DS). In the absence of normality, the data are expressed in median 
(M) and interquartile range (IQR). For quantitative variables, if the data presents a 
normal distribution, a T student test is used. In cases with no normality criteria, Mann-
Whitney U test. In qualitative variables, Chi-square and Fisher's exact test are used if 
more than 20% of the expected frequencies in the tables have a value less than 5. Finally, 
for comparisons of qualitative variables with quantitative variables, ANOVA or Kruskal-
Wallis are used. To compare time to hypnosis between the groups, Kaplan-Meyers curve 
is used. 

ICF_000.pdf: 
Impact of Propofol Dose Reduction in Relation to 
the Time Since Administration of Fentanyl During 
Anesthesia Induction 
 
NCT number: 04194151 
 
October 24th, 2017 
 
 


PATIENT INFORMATION AND INFORMED CONSENT 
Dear Patient: 
The purpose of this document is to inform you of the possibility to participate in a totally 
voluntary way in a research project that we are carrying out. We will explain the various aspects 
of the project, so you can decide if you want to participate. 
This is a research study on the time and doses administered for anesthetic induction, the time 
at which the optimal anesthetic depth is reached and the hemodynamic changes that this 
generates, which is completely foreign to any aspect related to the pathology for which you are 
being intervened. The participation in this trial, whose title is "Assessment of the reduction in 
the dose of propofol in relation to the time since the administration of fentanyl during anesthetic 
induction", is COMPLETE voluntary. 
The objective of this study is to assess whether it is possible to reduce the dose of propofol 
necessary for anesthetic induction when the time since administration of fentanyl is prolonged. 
As you have been informed previously by the anesthesiologist, you need the administration of 
general anesthesia for the surgery you are scheduled. For this, it is required to monitor your 
heart rate and blood pressure in a non-INVASIVE manner, among other parameters, to assess 
your hemodynamic state while you are asleep. 
The study consists of registering your data (age, sex, weight, antihypertensive medication -if you 
take any-, classification of anesthetic risk according to the American Society of Anesthesiology, 
heart rate, blood pressure and Bispectral Index value) before being asleep. The Bispectral Index 
monitor is a monitor that measures your brain activity using a sensor that sticks to the forehead 
to determine the degree of anesthetic depth. 
According to usual practice, venous access is achieved and anesthetic drugs will be administered 
at a timed interval and at clinical doses, recording your heart rate, blood pressure and the time 
it takes to reach the optimal anesthetic depth. 
Participation in this study is ABSOLUTELY VOLUNTARY and you may decide to withdraw 
permission to use your data at any time. 
Benefits and Risks 
You will not get any personal benefit from participating in this study, but the knowledge gained 
from this research can help improve the care of future patients. 
Because the drugs that will be provided to you are those that are routinely administered, no 
condition that could cause harm, pain or suffering will be altered, nor will your level of sedation 
be compromised. The risks of general anesthesia that have been previously explained in the 
Anesthesiology and Resuscitation office are not altered by this data record. 
Refusal to participate does not affect the care or relationship with your doctors. 
Confidentiality 
The information recorded in this study will be protected to maintain confidentiality according to 
current data protection laws. We will not provide any information that identifies you, your 
personal data will not be published in the scientific press without your authorization and will 
only be identified with investigation fines. 


According to the Organic Law of Protection of Personal Data (15/1999 of December 13), all 
personnel related to the study are obliged to protect the confidentiality of the data of the 
participants; and at any time you can exercise your rights of access, rectification, cancellation 
and opposition, send a written request accompanied by a photocopy of the official identity 
document to the Anaesthesiology and Resuscitation Service of the Hospital Central de la Defensa 
"Gómez Ulla", Glorieta del ejército s/n, 28047, Madrid (Madrid). 
The anesthesiologist Dr. Paula Agostina Vullo is at your disposal to answer any questions you 
may have, being your phone number +34 *** *** 151. 
In consecuense, 
I, D./Dña. ... ……………………………………………………………, of… .. years of age and with ID number 
……………… stated that he previously demonstrated the information described. Dr. Vullo has 
clearly informed me of the implications of my participation in this study. 
I understand that my participation is voluntary and that I can withdraw from the study whenever 
I want, without having to give explanations and without this having an impact on my medical 
care. 
 
Madrid,  ………………………………………… 20 …… 
 
 
……………………….. 
 
…………………………… 
Doctor  
 
 
Patient / Legal tutor