Analyzing the Relationship Between Rate of Induction and Perioperative Hypotension Using Propofol
Phase: PHASE3
Conditions: Hypotension on Induction
Sponsor: University of Toledo

NCT05415436 
PROTOCOL 
Analyzing the Relationship Between Speed 
Propofol is Given and Low Blood Pressure 
Dr. Scott Pappada 
University of Toledo Medical Center 
Toledo, Ohio 
080CT2024

ANALYZING THE RELATIONSHIP BETWEEN RATE OF 
INDUCTION AND PERIOPERATIVE HYPOTENSION USING 
PROPOFOL 
IRB #301220 
Scott Pappada Ph.D 
Department of Anesthesiology 
University of Toledo Health Science Campus 
3000 Arlington Avenue, Mailstop #1137 
Toledo, Ohio 43614 
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TABLE OF CONTENTS 
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Background: 
Propofol is one of the most common drugs used for induction and 
maintenance of general of anesthesia. The main advantage of propofol, which 
contributed to its popularity, is its rapid onset and short duration of action. When 
administered as an IV bolus, the clinical effects wane within a few minutes[1]. The 
main mechanism of action of propofol is its interaction with the GABA receptor; 
and it has a short duration of action due to rapid distribution into peripheral 
tissues[2]. 
One of the main disadvantages of propofol is iatrogenic hypotension, with 
an incidence as high as 68% [3-5], associated with increased requirement of 
vasopressor administration[6] and higher mortality and negative outcomes[7, 8]. 
One study reported that general anesthesia with propofol at doses 125 and 200 
ucg/kg/min decreases the mean arterial pressure from 8543 to 6945 and 6644 
mmHg, respectively[9]. 
Another author reported that increasing the mean propofol Cb 3.0 (0.9), 4.5 
(1.0), and 6.5 (1.2) ug ml71 decreases bispectral index spectrometry (BIS) 
measurements to 54 (13), 39 (8), and 29 (7), respectively. Increasing 
concentrations of propofol led to venous dilatation; and mean arterial pressure 
from 82 (12) to 75 (12) and 66 (10) mm Hg, respectively, at the three propofol Cb 
levels (P < 0.001)[10]. 
On the other hand, a prospective, double-blind, open-label, randomized 
study in the United States has reported only 17.4% incidence of propofol-induced 
hypotension[11]. 
There are multiple risk factors and comorbidities which increase the relative 
risk (RR) of propofol-induced hypotension. In his study, Abdelmonem et al. (2019) 
demonstrated that advanced age, higher APACHE II score, sepsis, diabetes, acute 
and chronic kidney diseases, cirrhosis, atrial fibrillation are associated with higher 
RR of Propofol induced hypotension development, when compared with the cohort 
group [34] 
Age is an independent factor associated with severe hypotension. A study 
reported that approximately half of patients sedated with propofol experienced 
hypotension are above the age of 60 [35]. 
It has been shown that age is the 
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strongest risk factor for propofol-induced hypotension, and propofol should be 
given with significant caution within certain age groups[12]. 
Multiple studies describe the mechanism of this phenomenon, yet the exact 
mechanism is fully unknown. Possible reasons of hypotension after propofol 
administration may be either due to propofol-mediated decreases in preload, 
cardiac output ané contractility[13, 14], decreased in afterload and systemic 
vascular resistance[15-20], or sudden cessation of sympathetic vasomotor 
activity[21-24]. The above described hypothesis is supported with the fact that a 
preoperative bolus of fluids helps maintain the hemodynamic stability during 
induction with propofol[25]. However, in animal models, propofol demonstrated a 
property of direct relaxation of vascular smooth muscle[26-33]. Moreover, this 
property of propofol most likely has been achieved via nitric oxide[28] and veins 
seems to be more sensitive than arterioles[26, 31]. 
An anonymous survey conducted at the Department of Anesthesiology at 
UTMC revealed that 63% of anesthesiologists starting their induction with the 
sequence of follow medications: Fentanyl-Lidocaine-Propofol-Succinylcholine. 
27% of them administer propofol within 10 seconds via manual push, 45% within 
10-20 seconds and less than 30% of anesthesiologists administer propofol in 60 
seconds or longer. 
Majority of anesthesiologists (45%) are calculating the dose of propofol 
based on ideal body weight and titrating it until desired hypnotic effect is achieve 
instead of administering of full pre-induction calculated dose (72%). 
This wide variability in anesthesiologic practice at The Department of 
Anesthesiology UTMC is based on training, experience, and a comfort level of the 
provider. Nevertheless, all anesthesiologic approaches mentioned above are 
acceptable and being safely used for routine daily management for years. 
Summary of Background: 
The pharmacokinetic and pharmacodynamic properties of propofol, such as fast 
onset of action, rapid distribution, smooth awakening, and low rate of 
nausea/vomiting make propofol the most preferable hypnotic medication for 
induction and maintenance of anesthesia. Compared to midazolam, propofol allows 
better and precise control of the depth of anesthesia with less side effects. 
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However, the induction of anesthesia with propofol is associated with hypotension 
with marked reduction of sympathetic outflow and plasma catecholamine levels. 
This side effect becomes more significant in elderly patients undergoing a surgical 
procedure. Thus, the study is required to evaluate the association between the 
speed of propofol administration and post-induction and intra-operative 
hypotension. 
Significance of the Study 
Considering the wide variety of current anesthesiologic management during the 
induction at our Department, we decided to conduct a study to evaluate the benefit 
of slow speed propofol induction. This prospective study will evaluate the 
influence on hemodynamic changes with a controlled, slow rate of induction of 
general anesthesia with propofol compared to the standard induction rate (manual 
push within 10-20 seconds). By gathering this information, we will be able to 
determine the optimal rate of induction in order to avoid propofol-related 
hypotension during elective surgeries. 
Study Objectives: 
Primary Aim 
To evaluate the association between induction rate using propofol and post- 
induction hemodynamic stability in patients. 
Secondary Aim 
To evaluate the necessity of inotropic or vasoactive medication use in the 
early post-induction period, required to correct propofol-induced hypotension. 
Tertiary Aim 
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To evaluate the association between hemodynamic stability, delay in 
surgical procedure start time, length of hospital stay, as well as early post-operative 
complications and 30-day mortality and morbidity. 
Primary Hypothesis 
We hypothesize that a slow rate of induction using propofol over at least two 
minutes may be associated with a lower incidence of post-induction and 
perioperative hypotension. In turn, this will result in less inotropic and vasoactive 
medication use in the early intra-operative phase. 
Secondary Hypothesis 
We hypothesize that hemodynamic stability during and after induction, less 
administration of vasoactive and inotropic medications is associated with less 
complications during early post-operative period, shorter length of hospital stay 
and a lower 30-day mortality. 
Study Designs: 
Cluster randomized, non-blinded, cohort trial. Study will be conducted, and 
patient will be enrolled at the main Operating Unit of The University of Toledo 
Medical Center, Toledo Ohio. 
Study Methods: 
Propofol can be administered during induction as fast (within 10-20 
seconds), as well as slow for 60 seconds and longer. Both types of inductions are 
being safely used at our department. To compare the benefit of slow speed 
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propofol induction on hemodynamic stability, we decided to compare two 
practices. 
We plan to compare the rate of propofol administration: a bolus within 
approximately 10-20 seconds vs. slow administration of propofol within 120 
seconds. The hypnotic properties of propofol will not be affected by the change, as 
propofol is approved by FDA for maintenance (continuous infusion) anesthesia. 
[FDA revised form: DIPRIVAN® (propofol) injectable emulsion, USP, 451094H Revised: April 2017 
[36]. 
As this study does not aim to change any anesthesiologic practice, but 
simply trying to compare difference in current practices, we are planning to apply 
to Institutional Review Board for patient consent waiver. Our rational behind this, 
is that we do not plan to add, or change any medication that anesthesiologist will 
plan to use for each patient. And the patient does not choose the provider, and with 
equal odd can be taken care of either one or another provider. 
On the morning of the surgery, eligible and consented subjects will be 
randomized into two groups: groups A and B. Randomization will be done in 
advance using Excel Randomization function with allocation 1:1 per groups: 
Sample size of 100, two groups, 50 patients in each group. After patient is 
consented by a research personnel, Patient will get the next randomization spot in 
the list. 
Group A: Staff anesthesiologist will calculate the dose of Propofol (Any 
patient, who was not planned to get Propofol for induction does not meet the 
Inclusion Criteria and will not be enrolled in this study). Current study has no 
intervention on Propofol dose calculation. The Research Member will ensure that 
the calculated dose of Propofol is being administered by a primary anesthesia 
provider intra-venously during 10-20 seconds via manual bolus per FDA approved 
administration speed (20-40 mg/per 10 seconds). 
Group B: Staff anesthesiologist will calculate the dose of Propofol (Any 
patient, who was not planned to get Propofol for induction does not meet the 
Inclusion Criteria and will not be enrolled in this study). Current study has no 
intervention on Propofol dose calculation. The Research Member will ensure that 
the calculated dose of Propofol is being administered by an anesthesia provider 
intra-venously during 120 seconds via Alaris Syringe Module. The reason of a 
syringe pump use is to eliminate any duration differences among patients in Group 
B; 
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After induction the hemodynamics, administered inotrop and vasoactive 
medication data will be collected for the first hour after induction. The research 
personnel will collect the information about the start of surgery, to compare 
possible delays in surgery starts between the groups, 30 days mortality and 
morbidity. All necessary information will be collected by using intra-operative 
Electronic Medical Record system, as well as Outpatient Athena Electronic 
system. 
Propofol has been used for decades in anesthesiology and ICU settings. It is 
being safely used as a bolus administration for induction (as stated in FDA form: 
20-40 mg for 10 seconds) as well as continuous intra-venous infusion for sedation 
of patients in ICU. Additionally, Total Intra-Venous Anesthesia (aka. TIVA) 
represents a constant prolong Intra-Venous Administration of IV anesthetics 
(nowadays Propofol is the drug of choice for TIVA) instead of volatile anesthetic 
as a sedation agent of general anesthesia. Considering that both fast bolus and 
continuous prolong Intra-Venous administration of Propofol has been safely used 
for decades, the research team hypothesize that: 
1. Group A represents the Propofol administration group with 
FDA approved 
administration rate of 20-40 mg/ per 10 seconds. Considering this fact, 
patients in group A are not different than any other patient receiving an 
anesthesia care for an elective surgery at UTMC. 
2. Group B patients are not in a higher risk associated with a longer Propofol 
administration (120 seconds) than any patient receiving a continuous 
prolong Propofol administration which is 
a common practice in medicine 
and has been safely used for years. 
For the primary randomization, Patient's MRN will be collected which will 
be kept in Key code document. The information of Biometric data (such as weight, 
age, type of surgery, ASA status, surgery start and end time, proprofol 
administration time),constant vital data (such as blood pressure, heart rate, 
saturation) as well as any vaso-active or inotropic medication (such as 
Phhenylephrine, Ephedrine, Vasopressine, Norepinephrine, Epinephrine, 
Dobutamine), as well as amount of opioid medications (such as Fentanyl, 
Hydromorphone) and intravenous fluids (such as Lactated Ringer, Normal Saline, 
Albumin) administered during the surgery will be collected and stored in a "Data 
Collecting Sheet" attached to this IRB form. Additionally, any antihypertensive 
medications taken prior to surgery will be documented on the data collection sheet. 
Antihypertensive medication taken the day of the surgery can become a 
confounder for hypotensive events during the induction of anesthesia. Thus, the 
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antihypertiensive medication history should be obtained for future data analysis 
and group stratification. 
No Identification data will be reflected on Data Collecting sheet but only 
randomization Key Code. 
All details regarding the hemodynamic changes, administration of vaso- 
active and inotropic medications will be collected post-factum by using the intra- 
operative electronic system at UTMC.. Collected data will be kept in HIPAA 
friendly storages locked and allowed to be accessed by the IRB approved 
personnel only. 
Collected raw data will be categorized, standardized, and provided to the 
statistician for the statistical analysis 
Statistical analysis: 
Assuming a standard deviation of 10 mm Hg, to have an 80% power at a 
significance level of 0.05 for a two-sided comparison, the sample size needed to 
detect a 10 mm Hg difference in mean arterial blood pressure (MAP) reduction is 
23 for each group. With 50 in each group, we will be able to detect such reduction 
even when the standard deviation is 15 mm Hg. And this will increase the power of 
the study up to 90%. 
Sample Size: 
Total of 100 people will be approached to consent for this study. We hope to 
enroll total of 100 patients with equal allocation of 50 patients in each group. 
Despite our statistical calculations have shown that total of 46 patient should be the 
minimum sample size, we decided to double this number to improve the power of 
the study and detection of even small changes in hemodynamics alterations. 
Eligibility Criteria: 
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Inclusion Criteria 
¢ 
Any patient from 18 till 80 years of age 
e 
Patient undergoing non-cardiac elective surgery 
e 
Duration of the surgery longer than one hour 
e 
Native/Fluent English speaker 
¢ 
Patients whose staff anesthesiologist planned to use Propofol as a primary 
anesthetic for induction 
Exclusion Criteria 
¢ 
Any patient admitted for non-elective surgery 
« 
Any patient undergoing cardiac surgery 
¢ 
Any patient younger than 18 years of age 
e 
Any patient older than 80 years of age 
« 
Any patient with history of severe heart disease (CHF with significant 
limitations of activity due to severe symptoms, prior heart surgery, atrial 
fibrillation etc.) 
e 
Any patient with pre-operative hemodynamic instability (e.g., Sepsis, 
Chronic Kidney Disease, Liver Cirrhosis) who requires constant or 
intermittent administration of vasoactive or inotropic medication to support 
vital signs (BP) 
e 
Any patient on vaso-active or inotrop medications in early pre-operative 
period (within 24 hours prior to the surgery) 
e 
Any patient who does not speak English or speaks with not fluently 
¢ 
Any patient with cognitive impairment or mentally incapacitation 
e 
Any pregnant or breastfeeding females 
e 
Any Patient whose staff anesthesiologist planned to use a primary anesthetic 
other than propofol 
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Ethical Consideration 
We will submit this protocol to our Institution Review Board. We will 
maintain confidentiality of patient data. Research personnel will store the paper 
copies of case report forms (CRFs) in locked cabinets. All study personnel will 
ensure no patient identifiers are present on any files transmitted. We shall also 
ensure de-identification of all data in final reports. 
All collected data will be processed and stored till full completion of the trial 
in HIPAA securely storages. After completion of the trial, data will be cleaned and 
sent for statistical analyzes, to compare the cardiac functionality of the heart during 
NAVA and SIMV ventilation modes 
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