Blood Loss and Visibility With Esmolol vs. Labetalol in Endoscopic Sinus Surgery: A Randomized Trial
Phase: PHASE2
Conditions: Chronic Sinusitis
Sponsor: The University of Texas Medical Branch, Galveston

 
 
    The University of Texas Medical Branch   
 
 
 
 
 
 
 
Title: Comparison of blood loss and intraoperative visibility between Labetalol and 
Esmolol: A randomized controlled trial 
 
 
Principal Investigator:  Mohamad R. Chaaban, MD, MSCR, MBA 
 
Funding Sponsor: Departmental  
 
IND number: N/A 
 
Version number and date: 1.0_01/23/2016   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
1. Introduction and Purpose 
 
Bleeding during endoscopic sinus surgery (ESS) affects the ability of the surgeon to 
identify key structures such as the skull base, orbit, nerves and major vessels. 
Rhinologists have examined multiple ways to decrease intraoperative bleeding as 
well as improve endoscopic visibility.  
 
This study hypothesizes that intraoperative blood pressure control with esmolol 
decreases blood loss and improves operative visibility during ESS as compared to 
labetalol. The effect will be objectively studied by comparing estimated blood loss 
and intraoperative visibility utilizing validated intraoperative bleeding/ visibility scores. 
In addition, patients will be stratified in accordance to their severity of their disease 
according to their Lund Mackay scores based on their CT scan findings that are 
routinely obtained prior to surgery. 
 
The short half-life and the ability of continuous infusion of esmolol provides a tighter 
control of intraoperative blood pressure. Additionally, its selective beta blockade 
avoids antagonizing the effect of the topical epinephrine vasoconstrictor that is used 
intraoperatively during ESS.   
 
If the study demonstrated a significant difference between the groups, it would 
potentially affect our selection of beta blockers during ESS. The potential benefits 
include providing safe, complete surgery and potentially decreasing cost. The 
complications that could potentially arise from poor intraoperative visibility include 
CSF leak and orbital injuries that could lead to lead to blindness. 
 
2. Background  
 
During ESS, bleeding from the mucosal surfaces often interferes with visualization of 
the anatomy and increases the small risks of serious complications such as injuring 
the skull base leading to a cerebrospinal fluid leak or an injury to the eye. 
Additionally, the bleeding interferes with visualization during the procedure and a 
reduction of the bleeding would result in greater ease and thoroughness of the sinus 
surgery.  
 
Historically, several ways have been used to decrease intraoperative bleeding. 
Controlled hypotension (keeping the mean arterial pressure between 50 and 60) has 
been used using either the anesthetic agents alone or using either sodium 
nitroprusside or esmolol drips [1-3].The use of these medications increases the risk 
of serious side effects such as cyanide toxicity and myocardial depression. Recent 
studies have shown that controlled hypotension is associated with increased 
morbidity and mortality. The latter was found to be in the range of 20 to 60 deaths in 
100,000 patients mainly as a consequence of ischemic organ failure [4]. There is also 
good evidence that decreasing the MAP below 70 can even increase intraoperative 
bleeding due to local arteriolar vasodilatation which results from decreased blood 
flow to the tissues, increased local carbon dioxide concentration and decreased pH. 

[3,5].Another mechanism that can explain this is an increase in cardiac output during 
controlled hypotension resulting from reflex tachycardia specially with the use of a 
pure vasodilator like sodium nitroprusside [6]. 
 
There are multiple factors which contribute to blood loss during surgery, including, 
but not limited to surgical and anesthetic technique. At the University of Texas 
Medical Branch, the endoscopic surgical technique is fairly uniform and comparable 
to practices throughout the world. Most of the endoscopic sinus surgery is performed 
under general anesthesia. There is a suggestion among ENT physicians and 
anesthesiologist that different blood pressure medications affect intraoperative 
visibility and possibly lead to less intraoperative blood loss. It is also thought that 
intraoperative topical decongestants (specifically epinephrine) work by binding to 
alpha receptors. Labetalol, which is an alpha and beta blocker, may interfere with the 
effect of this topical decongestant. [7-9] The goal of this investigation is to formally 
evaluate this notion utilizing two very commonly used blood pressure medications: 
Labetalol and esmolol. This study does not use any medications that are not routinely 
used during endoscopic sinus surgery at the University of Texas Medical Branch. 
 
3. Concise Summary of Project:  
 
Subjects who are scheduled for routine endoscopic sinus surgery will be recruited 
(n=40). The subjects in this prospective study will be randomized to either receive 
labetalol or esmolol.  Current standard of care in preventing hypertension during 
sinus surgery due to stimulation and injection and application of sympathetic agents 
includes, narcotic administration, increasing volatile agent (Sevoflurane), esmolol, 
labetalol and other agents (hydralazine, nicardipine and nitroprusside). It is not 
known the impact these anti-hypertensive agents have on blood loss or blood in 
surgical field. 
Intraoperatively, topical epinephrine pledgets will be used for decongestion similar to 
what is done routinely in endoscopic sinus surgery. 
Intraoperative visibility will be scored utilizing two validated endoscopic visbility 
scores. In addition, at the end of surgery the estimated blood loss will be calculated 
by subtracting the amount of irritagation used during surgery from the amount of 
blood in the suction canisters. 
In addition, the surgical video will be recorded and the intraoperative visibility will also 
be recorded by an independent observer. 
In addition to the demographics and our primary outcome, secondary outcomes will 
be collected including duration of anesthesia, duration of surgery, final CO2, 
postoperative bleeding, visit to the ED following discharge, need for medical attention 
following discharge, surgeon satisfaction on a likert scale (1-10), need for surgical re-
intervention, and pain score after surgery, as well as time spent in recovery, use of 
anti-emetics postop, and nurses notes on as regards to pain and recovery. 
 
Subjects may be excluded from the study if the anesthesiologist deemed it necessary 
that the protocol drug can not be used on the patient for any reason. Otherwise, it is 
expected that the surgeries will be routinely performed and the study outcome 

variables do not interfere with the routine.  
 
 4. Study Procedures: 
 
This will be a prospective randomized study comprising subjects (n=40) over 18 
years of age scheduled for ESS. The inclusion criteria will be male or female patients 
with ASA physical status 1 (normal otherwise healthy patient) or 2 (patient with mild 
systemic disease) and patients who have chronic sinusitis with or without nasal 
polyps.  Exclusion criteria include: pregnancy, asthma, obstructive pulmonary 
diseases, sinus bradycardia and severe bradycardia, sick sinus syndrome, heart 
failure, end-stage renal disease, stroke, diabetes mellitus, preoperative use of 
nonsteroidal anti-inflammatory medications (NSAIDS) or aspirin (ASA) within the last 
week, and a body mass index (BMI) greater than 40. Additionally, any patient that the 
anesthesiologist deems unfit for randomization will also be excluded.  
 
We will randomize the patients in blocks of 4 to determine the impact of a specific 
study drug (either esmolol (n=20) or labetalol (n=20) along with sevoflurane to control 
blood pressure on bleeding. The patients will be classified according to their Lund 
Mackay scores, which will be obtained from their routine CT scan performed prior to 
their surgery. 
 
Written informed consent will be obtained. On arrival to the operating room, all the 
patients will be monitored as per usual anesthesia routine. Patients in both groups 
will be induced using 1-2 mg midazolam PRN anxiety, 1-3 mcg/kg fentanyl, 20-40 mg 
lidocaine, 1-2 mg/kg propofol, and 0.05-0.1 mg/kg vecuronium. Thereafter, 
maintenance with general anesthesia will receive 1-2% of sevoflurane (end expired). 
Both groups may receive fentanyl throughout the case at the discretion of the 
anesthesiologist. The dose of fentanyl is not to exceed 5 mcg/kg. The patient's mean 
arterial blood pressure (MAP) will be maintained at 70-80 mm Hg (80 for 
hypertensive patients) by first adjusting the sevoflurane concentration within their 
range (between 1-2 percent for the sevoflurane. If sevoflurane is maximized (Fe sevo 
>2%) and the target MAP is not achieved, then the patients will receive either 
esmolol or labetalol (study drug will be blinded for surgeon). 
  
The surgical procedure will not be altered. All patients will be placed supine with 6 
degrees head up the entire procedure. Local vasoconstriction will be performed first 
with bilateral endonasal application of oxymetazoline soaked pledgets for 2 minutes.   
This is followed by placing topical epinephrine pledgets (1:1000) throughout the 
duration of the case. Our primary Outcome measures will include 1) intraoperative 
visibility utilizing two validated bleeding scores (Wormald and Boezart score) 
intraoperative visibility (1 minute, and every 20 minutes thereafter)  2) estimated 
blood loss at the of end of surgery which will be calculated by subtracting the amount 
of irrigation used from the total blood in the suction canisters. 
Blood loss will be evaluated by the blinded rhinologist (MRC) and an independent 
observer who will review the un-identified endoscopic surgical videos.   
 

In addition to the demographics and our primary outcome, secondary outcomes will 
be collected including duration of anesthesia, duration of surgery, final CO2, 
postoperative bleeding, visit to the ED following discharge, need for medical attention 
following discharge, need for surgical re-intervention, Bispectral index (BIS) 
monitoring intraoperatively (taped on patient forehead), surgeon satisfaction score on 
likert scale (1-10), and pain score after surgery, as well as time spent in recovery, 
use of anti-emetics postop, and nurses notes on as regards to pain and recovery. All 
the medications used in this study are used as part of the standard of care when 
patients develop high intraoperative blood pressure as a result of the usuage of the 
topical decongestants. 
 
Blood pressure control medications: 
Labetalol is a mixed adrenergic receptor antagonist (beta 1> alpha 1 blocker). If 
randomized, the anesthesiology investigator will obtain 3 bottles of labetalol (100 mg 
in 10 mL). Per protocol, aliquots of 10-30 mg of labetalol will be administered SIVP if 
MAP > 80 and sevoflurane [2%]. Initial dose will be 20 mg (within 2 min), followed by 
infusion of 0.25-0.5 µg/min. Maximum dose =  300 mg for case duration. If maximum 
dose is acheived, other agents per discretion of the anesthesiologist will be 
administered.  
 
Esmolol is a specific beta adrenergic antagonist (beta 1>> beta 2). If randomized, the 
anesthesiology investigator will obtain a 2500 mg in 20 mL vial. Esmolol will be 
diluted in 250 mL 0.9% NaCl to achieve a concentration of 10 mg/mL. Per protocol, 
an infusion of esmolol at a rate of 0.1 mg/kg/min if MAP > 80 and sevoflurane [2%]. 
The dose can be titrated up to 0.3 mg/kg/min. If after 30 min, the esmolol dose is 
>0.3 mg/kg/min other agents per discretion of the anesthesiologist will be 
administered.  
 
 
5. Sub-Study Procedures: 
N/A 
 
6. Criteria for Inclusion of Subjects 
 
The inclusion criteria will be male or female patients with ASA physical status 1 
(normal otherwise healthy patient) or 2 (patient with mild systemic disease) and 
patients who have chronic sinusitis with or without nasal polyps and who are 
scheduled for a routine ESS. 
 
7. Criteria for Exclusion of Subjects  
 
Exclusion criteria include: pregnancy, asthma, obstructive pulmonary diseases, sinus 
bradycardia and severe bradycardia, sick sinus syndrome, heart failure, end-stage 
renal disease, stroke, diabetes mellitus, preoperative use of nonsteroidal anti-
inflammatory medications (NSAIDS) or aspirin (ASA) within the last week, and a body 
mass index (BMI) greater than 40.  Subjects may be excluded from the study if the 

anesthesiologist deemed it necessary that the protocol drug cannot be used on the 
patient for any reason. Otherwise, it is expected that the surgeries will be routinely 
performed and the study outcome variables do not interfere with the routine. 
 
8. Sources of Research Material 
 
Intraoperatively, a bleeding score will be used (validated questionnaire) based on the 
visibility. In addition, at the end of the surgery, the estimated blood loss will be 
calculated. All other secondary outcomes will be collected following the completion of 
surgery. These will be obtained from the medical record (duration of anesthesia, 
duration of surgery, final CO2, Bispectral index (BIS) monitoring, postoperative 
bleeding, visit to the ED following discharge, need for medical attention following 
discharge, need for surgical re-intervention, and pain score after surgery, as well as 
time spent in recovery, use of anti-emetics postop, and nurses notes on as regards to 
pain and recovery). 
 
9. Recruitment Method and Consenting Process: 
 
The informed consent for the study will be obtained either in the preoperative clinic 
visit or on the day of the surgery in the pre-operative holding area. Informed consent 
for the study will be separate from the surgical consent. The name of the attending 
surgeon will be written on the study consent together with the name of the attending 
anesthesiologist. The informed consent will then be included in the patients' charts. 
 
10. Potential Risks: 
 
The risks and benefits of the study will be discussed with the patient on obtaining 
written informed consent. Consent for surgery and anesthesia will be done as usual. 
The study adds no risks above those associated with risks of surgery and risk of 
anesthesia. Neither anesthetic technique used here breaches the standard of care 
nor is the surgical technique not altered. There is no clear evidence of any difference 
in between the two groups in the literature in regards to their effect on recovery time 
or their gastrointestinal side effects (nausea and vomiting). 
 
11. Subject Safety and Data Monitoring 
 
Monitoring of the patients will abide by the standards set forth by the American 
Society of Anesthesiology.  Additionally, the standard surgical procedures will be 
applied in this study.   
 
Any adverse event will be reported immediately to the IRB and FDA if it was drug 
related.  Given that the medications used in this study are used routinely by 
anesthesiologists, the reported adverse event will unlikely be related to the study 
itself.  
 
12. Procedures to Maintain Confidentiality 

 
As a patient enters the study, the investigator will assign that patient to the next 
sequential study code number available. All data and subject information will be 
stored in the investigator’s laboratory in locked file cabinets or on a secure computer. 
Access to the data will be restricted to the investigators, nurses, and technicians 
involved in this project.  
13. Potential Benefits 
 
The main benefit is that if there is a difference between the groups then they will have 
less blood loss. The choice of medication for blood pressure control intraoperatively 
will likely be implemented should the results demonstrate any difference between the 
groups. In the event that there was no difference between the groups, then the 
medications can continue to be used without the concern of impaired visibility to the 
endoscopic surgeon. 
 The study adds no risks above those associated with risks of surgery and risk of 
anesthesia. Neither anesthetic technique used here breaches a standard of care nor 
is the surgical technique altered. There is no clear evidence of any difference in 
between the two groups in the literature in regards to their effect on recovery time or 
their gastrointestinal side effects (nausea and vomiting).  
 
14. Biostatistics 
 
Accurate power analysis cannot be done since there is a lot of controversy in the 
older studies. For this reason, our number of patients (N=40) to be included in the 
study was inferred based on the estimated difference in the mean of blood loss 
between the groups as being 110 ml and an estimated standard deviation of the 
mean between the two groups to be 150 and 200 respectively. 
 
If the results of the two groups stratified didn't show a normal distribution, then they 
will be compared using the Wilcoxon rank sum test with P value significant ≤0.05. If 
the results were normally distributed, then a student t -test will be used with P value 
significant ≤ 0.05. 
 
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