Abstract

Purpose

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Propofol is the
most commonly used intravenous anesthetic agent for daily anesthesia due to its
soft induction and fast recovery properties 1,2. However, hypotension that
occurs in induction is the most common disadvantage 3. Several
methods have been used to treat hypotension premeptively such as volume
expanders, physical methods to increase venous return and vasopressors 3,4. This
study is conducted to determine the effectiveness of granisetron (1 mg) in
prevention of hypotension and bradycardia in general anesthesia patients.

Methods

     After Institutional
Ethics Committee approval and written informed consent (Ref no 28/19,
04/04/2016) were obtained, and the 140 patients, under general anesthesia were
recruited in this study. Group G (n=70) received 1 mg granisetron diluted in 5
ml of saline and Group C (n= 70) received 5 ml of saline before 5 minute from
anesthesia induction. Sistolic blood pressure (SBP), diastolic blood pressure
(DBP), mean blood pressure (MBP), heart rate (HR) and  peripheral oxygen saturation ( SpO2)
are measured and recorded 3 minutes after induction and 1,5
minutes after intubation and every 5 minutes during operation.

Results

There were no statistically significant
difference in hemodynamic variables (SBP, DBP, MBP and HR) between the groups
on 3th minute after induction (p>0.05). The mean blood
pressure was decreased 22 patients in group C and 8 patients in group G compared
to baseline values in 10th minute after intubation.

Conclussion

               Granisetron prevents hypotension on mean blood pressure after the reverse trendelenburg position and CO2 insufflation in 10th minute. It can be use safely in laparoscopic cholecystectomy due to its beneficial effects.

 

 

Introduction

               Propofol
is the most commonly used intravenous anesthetic agent for daily anesthesia due
to its soft induction and fast recovery properties 1,2. However, hypotension
that occurs in induction is the most common disadvantage 3. The hypotensive
effect of propofol was attributed to a combination of venous and arterial
vasodilatation, a decrease in systemic vascular resistance and / or cardiac
output, which was due to impairment of the baroreceptor reflex mechanism and
depression of myocardial contractility 4.

 

               Preemptive treatments are important to reduce hemodynamic side effects 5. Several methods have been used to treat hypotension preemptively such as volume expanders, physical methods to increase venous return and vasopressors 3,4. 5HT3 antagonists have been widely used to prevent postoperative nausea and vomiting (PONV) (6). Granisetron is a serotonin 5HT3 receptor antagonist. Ondansetron used for this reason was found effective in preventing hypotension after spinal and general anesthesia 7. There are mechanoreceptors responsible for the Bezold-Jarish reflex that lead to systemic hypervolemia and hypovolemia, as well as serotonin-sensitive chemoreceptors in the heart wall 8. Hypotension after post-spinal anesthesia and stimulation of this reflex was caused by serotonin 7.                 Laparoscopic cholecystectomy has become the gold standard for cholelithiasis and it’s performed under general anesthesia. Laparoscopic cholecystectomy causes hemodynamic changes such as decreasing preload, compression on vena cava inferior. These effects are correlated with increased intraabdominal pressure due to pneumoperitoneum 9-16.

            This
study is conducted to determine the effectiveness of granisetron (1 mg) in prevention
of hypotension and bradycardia in laparoscopic cholecystectomy patients under general
anesthesia.

Methods

     Institutional
Ethics Committee approval and written informed consent (Ref no 28/19,
04/04/2016) were obtained, and the study was registered in clinicaltrials.gov
(NCT03180229). One hundred and fourty American Society of Anesthesiologists  (ASA) status I–II patients, aged 18 to 65
years, undergoing elective laparoscopic
cholecystectomy surgery under general
anesthesia were randomly allocated to two groups with sealed envelope
technique. Patients
with a history of cardiorespiratory or renal disorders, acute pancreatitis
disease and cognitive disorders were excluded from the study. Patients who have
passed to open surgery intervention were excluded.

               Peripheral venous catheterizations of patients were performed with 20 gauge needles and Ringer lactate (2 ml/kg) was administered before operation during fasting period. Standart monitorization were administered to all patients. After recording baseline heart rate and blood pressure, patients were randomly divided into two groups. Group G (n=70) received 1 mg granisetron diluted in 5 ml of saline and Group C (n= 70) received 5 ml of saline before 5 minute from anesthesia induction. Patients in both groups did not receive any premedication. Anaesthesia was induced with propofol 2.5 mg/kg. i.v. sistolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), heart rate (HR) and  peripheral oxygen saturation ( SpO2) are measured and recorded 3 minutes after induction and 1,5 minutes after intubation and every 5 minutes during operation. All patients received fentanyl 1 ?g/kg and rocuronium 0.8 mg/kg as neuromuscular blockade before intubation. Anesthesia was maintained with sevoflurane 2% in 50% N2O-50% O2. Controlled ventilation continued with a rate of 12 breath/min and a tidal volume of 6-8 ml/kg aiming for an end-tidal carbon dioxide (EtCO2) of 35-40 mmHg without positive end Positive End Expiratory Pressure (PEEP). Maintenance fluid of ringer lactate was infused at 5-10 ml/kg/h during operation in both groups. Hypotension was considered to be 25% decrease from baseline measurement. If hypotension was occured vasopressors (5 mg doses of ephedrine) treatments were administered. Intubation quality was assessed by Evans score (Table 1). At the end of surgery, neuromuscular blockade was antagonized with 0.01 mg/kg atropine and 0.03-0.05 mg / kg neostigmine. The patients were observed in the Post Anesthesia Care Unit for 30 minutes and then transfered to their ward.  

 

Statistical methods

Statistical Package for Social Sciences
(SPSS) software (version 22.0, SPSS, Inc, Chicago, IL, USA) was used for the
statistical analysis. Numerical variables were summarized with mean ± standard
deviations. Qualitative variables were expressed as numbers and percentages.
Differences in numerical variables among the groups and intra-groups were
examined by a t test in independent groups. 
Differences in quality variables in ASA status between groups were
examined using the chi-square test. Differences in SBP, MBP, DBP, HR, SpO2
and EtCO2 within and between groups were investigated by a
repeated measures of variance analysis. The statistical significance level was
considered p 0.05). The number of patients who are showing a decrease
in mean blood pressure on 10th minute to baseline value were
significantly different between the groups (p 0.05).  Both
groups were similar in respect to Evans Score (p>0.05) (Table 2).

 

Discussion

In this study we showed that preemptive
granisetron lowered the tenth minute hypotension after propofol induction in
adult patients. As far we are concerd this is the first study administiring
granisetron in adult patients for preventing hpotension after induction under
general anesthesia.

Hypotension occurs generally during
spinal anesthesia. Hypotension results from that decrease venous return and
decrease cardiac output from a decrease in systemic vascular resistance or from
a combination of both 17.  Bradycardia
and hypotension from stimulation of cardiac chemoreceptor and mechanoreceptor
were established.18,19 Spinal anesthesia related triggering of BJR is known
to result from stimulation of 5-HT3 receptors in vagal nerve endings.20 in previous
study showed that the effects of serotonin administration on systemic
hemodynamics variable on rabbits. It revealed that hypotension and bradycardia
similar to that associated with BJR occurred.21 5-HT3 receptors have been associated
with as anxiety, vomiting and stress-induced gastrointestinal problems.22 Another
study showed that grainsteron was significantly prevented paradoxical
bradycardia and a fall in the systolic blood pressure (SBP) due to bleeding.23

Several methods have been used to prevent
hypotension after induction. Norihito Kitagava et al. 24 planned to block
parasympathetic activity in order to prevent bradycardia following propofol
induction and used 0.01 mg / kg of atropine for this purpose. In their study
atropin group had a increase in HR but control groups HR was decreased. In both
group arterial blood pressure decreased after induction. They showed that
atropin which was used before induction of propofol has found to reduce
cardiovascular depression. In the terms of same purpose we used granisetron but
we didnt find any effects of prevention hypotension after induction but
granisetron lowered the tenth minute hypotension .

In our study, we included adult patients
(18-65yr) as elderly population lacks dramatic response to hypotension. Severe
hypotension has similar effects in adult and elderly patients. Turner et al. 25
have previously found that fluid infusions are ineffective in preventing
propofol induced hypotension. Darval et al. 26 warmed their patients with
conventional air one hour before induction but they couldn’t prevent
hypotension. Yin et all. used phenylephrine at two different doses (200 and 100
mcg) before induction and found that 200 mcg phenylephrine more effective than
100 mcg in attenuating propofol induced hypotension. In our study granisetron
was used and in thirth minute after induction there was no significant
difference between groups but prevent hypotension in ten minute after induction.

Özkoçak et al. 27 administered 2 mg /
kg propofol with 0.5 mg/kg ketamine or 70 ?g/kg  ephedrine before induction and compared their
effect on hypotension. In this study, they showed that ketamine and ephedrine
had smilar effects on hypotension after induction. In that study they showed
that administering ketamine 0.5 mg/kg dose one minute before propofol
induction, prevented hypotension after induction and also prevented
hypertension after intubation. We administered granisetron for that similar
purpose. But we did not find any effect on induction hypotension. We found that
there weren’t significant difference after intubation.  

When serotonin is
administered iv, vasoconstriction and consequent increase in preload causes
blood pressure elevation. Golparvar et al. 7 have shown that ondasterone used
before induction in an elderly patient population is effective in preventing
hypotension. We used granisetron, another 5HT3 antagonist in our
study, but we did not find any effect on post-induction hypotension. This might
be caused by our patients age range. But at the same time we found that the
variable of mean blood pressure in 10th minute after induction. Hemodynamic
changes due to laryngoscopy are caused by the depth of anesthesia. The high
level of serotonin may play a role in this effects 28. PRST score (pressure,
rate, sweating, tears) was defined by Evans and proposed for the detection of
inadequate depth of anesthesia.  The control parameter value was recorded before
propofol induction. Evans scores parameters determine the total score which can
range from 0 to 8. Inadequate depth of anesthesia is scored as more than three 29.
In our study the scores were smilar in both groups after intubation (Table 2).

            In addition, hypotension caused by propofol has a peak
effect after 2-3 minutes of induction. For this reason,
granisetron administration was performed five minutes before induction and
based on the blood pressure value at 3 minutes after induction. There is no
study for the best time interval for granisetron administration for prevention
of hypotension after induction. The exact mechanism of granisetron preventing
hypotension after induction in adult patients is unknown and can’t be explained
by BJZ reflex since 5HT3 receptors are located intracardiac 30,31. After
administration of granisetron, no side effects was observed in blood pressure
and heart rate measurements. When the blood pressure and heart rate values
??were compared, we could not find any statistically significant difference in
3th minute after induction between the groups. But in 10th
minute after induction granisetron administering prevented hypotension in ten minute after
induction.

                                                                                                                                        

James et
al. 3 performed graniosetron prior to the tilt test and they found that it
reduced the early sympathetic component of the syncope with less decrease in systolic
artery pressure. In our study, there were a significant
decreased in hypotension at 10th minute after taking the patients to
the reverse trendelenburg position after CO2 insufflation in granisetron group (Table
5). Although we can not
reveal its mechanism precisely, we think that the decrease in preload after
vena cava pressure with increased intraabdominal pressure increase is due to
the fact that we have eliminated the effect of the heart reflex because we have
blocked intracardiac 5HT3 receptors.

Conclusion

               Granisetron prevents hypotension on mean blood pressure after the reverse trendelenburg position and CO2 insufflation in 10th minute. It can be use safely in laparoscopic cholecystectomy due to beneficial effects.